SH3KBP1

Summary

SH3KBP1 (SH3 domain containing kinase binding protein 1, HGNC:13867) is a protein-coding gene on chromosome Xp22.12, encoding SH3 domain-containing kinase-binding protein 1 (Q96B97). Adapter protein involved in regulating diverse signal transduction pathways.

This gene encodes an adapter protein that contains one or more N-terminal Src homology domains, a proline rich region and a C-terminal coiled-coil domain. The encoded protein facilitates protein-protein interactions and has been implicated in numerous cellular processes including apoptosis, cytoskeletal rearrangement, cell adhesion and in the regulation of clathrin-dependent endocytosis. Alternate splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 30011 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 61 (Moderate, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 549 total — 2 pathogenic
• Phenotypes (HPO): 11
• MANE Select transcript: NM_031892

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13867
Approved symbol	SH3KBP1
Name	SH3 domain containing kinase binding protein 1
Location	Xp22.12
Locus type	gene with protein product
Status	Approved
Aliases	CIN85
Ensembl gene	ENSG00000147010
Ensembl biotype	protein_coding
OMIM	300374
Entrez	30011

Gene structure

Transcript identifiers

Ensembl transcripts: 56 — 27 protein_coding, 13 nonsense_mediated_decay, 9 retained_intron, 7 protein_coding_CDS_not_defined

ENST00000379697, ENST00000379698, ENST00000379716, ENST00000379726, ENST00000397821, ENST00000431164, ENST00000432234, ENST00000477102, ENST00000494961, ENST00000699666, ENST00000699667, ENST00000699668, ENST00000699669, ENST00000699670, ENST00000699671, ENST00000699672, ENST00000699673, ENST00000699674, ENST00000699675, ENST00000699676, ENST00000699677, ENST00000699678, ENST00000699679, ENST00000699680, ENST00000699720, ENST00000699721, ENST00000699722, ENST00000699723, ENST00000699724, ENST00000699725, ENST00000699726, ENST00000699727, ENST00000699728, ENST00000699729, ENST00000699730, ENST00000699731, ENST00000699732, ENST00000699733, ENST00000699734, ENST00000699735, ENST00000699736, ENST00000699737, ENST00000699738, ENST00000699739, ENST00000699740, ENST00000699741, ENST00000699742, ENST00000699743, ENST00000699744, ENST00000699745, ENST00000878923, ENST00000970301, ENST00000970302, ENST00000970303, ENST00000970304, ENST00000970305

RefSeq mRNA: 13 — MANE Select: NM_031892 NM_001024666, NM_001184960, NM_001353890, NM_001353891, NM_001353892, NM_001353893, NM_001353894, NM_001353895, NM_001353897, NM_001410756, NM_001410757, NM_001410758, NM_031892

CCDS: CCDS14193, CCDS35213, CCDS55383, CCDS94565, CCDS94566, CCDS94567, CCDS94568, CCDS94569, CCDS94571, CCDS94572, CCDS94573, CCDS94574, CCDS94575

Canonical transcript exons

ENST00000397821 — 18 exons

Exon	Start	End
ENSE00001200111	19695612	19695741
ENSE00001200119	19706881	19706984
ENSE00001632685	19537717	19537780
ENSE00001659172	19541925	19542193
ENSE00001670343	19549974	19550083
ENSE00001696322	19569103	19569188
ENSE00001709790	19746318	19746441
ENSE00001757635	19545922	19546050
ENSE00001781910	19588643	19588802
ENSE00001789519	19836125	19836282
ENSE00001938509	19533977	19536458
ENSE00002713245	19683823	19684028
ENSE00002725685	19887307	19887600
ENSE00003475589	19592067	19592147
ENSE00003512133	19631864	19631958
ENSE00003516036	19594949	19595000
ENSE00003643144	19645400	19645475
ENSE00003661767	19607938	19608045

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 99.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.6427 / max 2537.7375, expressed in 1763 samples.

FANTOM5 promoters (26 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198655	11.5172	1696
198654	10.2288	1428
198625	5.1734	880
198640	4.4043	418
198653	3.5199	747
198627	1.5507	475
198652	0.4457	209
198626	0.4267	182
198624	0.4150	176
198639	0.3112	96

Top tissues by expression

256 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.47	gold quality
left ventricle myocardium	UBERON:0006566	98.84	gold quality
ileal mucosa	UBERON:0000331	98.41	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.46	gold quality
upper arm skin	UBERON:0004263	97.36	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.32	gold quality
inferior vagus X ganglion	UBERON:0005363	97.20	gold quality
dorsal plus ventral thalamus	UBERON:0001897	97.12	gold quality
subthalamic nucleus	UBERON:0001906	96.90	gold quality
oocyte	CL:0000023	96.85	gold quality
blood	UBERON:0000178	96.70	gold quality
leukocyte	CL:0000738	96.68	gold quality
monocyte	CL:0000576	96.67	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.60	gold quality
colonic mucosa	UBERON:0000317	96.56	gold quality
bone marrow cell	CL:0002092	96.54	gold quality
cartilage tissue	UBERON:0002418	96.33	gold quality
kidney epithelium	UBERON:0004819	96.09	gold quality
myocardium	UBERON:0002349	96.06	gold quality
ventral tegmental area	UBERON:0002691	95.89	gold quality
pancreatic ductal cell	CL:0002079	95.71	gold quality
trabecular bone tissue	UBERON:0002483	95.69	gold quality
lymph node	UBERON:0000029	95.58	gold quality
medulla oblongata	UBERON:0001896	95.58	gold quality
granulocyte	CL:0000094	95.56	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.54	gold quality
superior vestibular nucleus	UBERON:0007227	95.31	gold quality
corpus callosum	UBERON:0002336	95.13	gold quality
vena cava	UBERON:0004087	95.11	gold quality
substantia nigra pars compacta	UBERON:0001965	95.07	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	18.15
E-CURD-112	yes	13.34
E-ANND-3	yes	11.41
E-CURD-119	yes	4.19

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA3, SOX10

miRNA regulators (miRDB)

133 targeting SH3KBP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-12133	99.92	71.82	2006

Literature-anchored findings (GeneRIF, showing 40)

• Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors (PMID:11894095)
• The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met (PMID:11894096)
• CIN85 participates in Cbl-b-mediated down-regulation of receptor tyrosine kinases (PMID:12177062)
• Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors. (PMID:12218189)
• Cd2 antigen is linked to CAPZ via this protein and CMS. (PMID:12690097)
• adaptor protein SETA (CIN85) and its binding partner AIP1 are involved with the cytoskeleton and in the regulation of cell adhesion (PMID:12771190)
• forms complexes with endonucleases in HEK293 cells (PMID:12946264)
• CIN85 association with Dab2 is essential for its recruitment to clathrin coat and appears to be modulated by growth factor stimulation (PMID:14596919)
• CIN85 (SH3-domain kinase binding protein 1) associates with TNF receptor 1 via Src and modulates TNF-alpha-induced apoptosis. (PMID:15707590)
• Data show that infected cell protein 0 (ICP0) binds CIN85 in a reciprocal manner and that the complexes pulled down by ICP0 also contain Cbl. (PMID:15824310)
• CIN85 might play an important role in HSV-1 infection. (PMID:16223483)
• Taken together, these results indicate a novel role for CIN85 in the regulation of cellular stress response via the MAPK pathways. (PMID:16256071)
• CFBP is a novel tyrosine-phosphorylated protein that might function as a regulator of CIN85/CD2AP (PMID:16895919)
• CIN85, a Cbl-interacting protein, is a component of AMAP1-mediated breast cancer invasion machinery. (PMID:17255943)
• unexpected role of 3BP2 in endocytic and cytoskeletal regulation through its interaction with CIN85 and HIP-55 (PMID:17306257)
• CIN85 is expressed as multiple isoforms that share the coiled-coil domain, suggesting that heterotypic interactions with CMS provides a mechanism to regulate CMS binding to F-actin and thus for modulating dynamic rearrangements of the cytoskeleton. (PMID:17606992)
• a new role for CIN85 in regulating Syk protein levels in RBL-2H3 cells through the activation of the ubiquitin-proteasome pathway and provide a mechanism for this regulation involving c-Cbl ligase activity. (PMID:17675467)
• identified a polyproline-arginine sequence in the pTalpha cytoplasmic tail that interacted in vitro with SH3 domains of the CIN85/CMS family of adaptors, and mediated the recruitment of multiprotein complexes involving all (CMS, CIN85, and CD2BP3) members (PMID:17823309)
• H-Ras interacts with Spry2-binding partners, c-Cbl and CIN85, in a Spry2-dependent manner. (PMID:18048363)
• These results suggest that endogenous Ruk/CIN85 may be involved in regulation of specific membrane trafficking processes. (PMID:18266907)
• Results suggest that competition between Cbl and ubiquitin binding to CIN85 regulates Cbl function and EGFR endocytosis. (PMID:18680311)
• Epidermal Growth Factor stimulation increases association of Cbl and Ruk/CIN85, which is dependent on tyrosine phosphorylation of the C-terminal region of Proto-Oncogene Proteins Cbl. (PMID:19166927)
• detailed high-resolution solution structural study of CIN85A and CIN85B binding to proline-arginine peptides derived from the cognate ligands Cbl and Cbl-b (PMID:19268472)
• The ORF3 protein of hepatitis E virus was found to interact with CIN85 and compete with the formation of the growth factor receptor-Cbl-CIN85 complex, resulting in the reduced ubiquitination of CIN85. (PMID:20130058)
• Ruk/CIN85 induces PAI-1 expression via modulation of HIF-1alpha stability (PMID:20216986)
• CIN85 binding to a C-terminal motif within hTTP leads to the increased phosphorylation of hTTP, possibly through enhanced association with MEKK4 (PMID:20221403)
• Coexpression of CIN85/Ruk(L) with CD2AP led to a decreased binding of CIN85/Ruk(L) to nephrin and podocin, which indicates a functional competition between CD2AP and CIN85/Ruk(L). (PMID:20457601)
• High CIN85 is associated with the development and progression of head and neck squamous cell carcinoma. (PMID:20927317)
• ARAP1 associated with CIN85 affects epidermal growth factor receptor endocytic trafficking. (PMID:21275903)
• the ubiquitination and degradation of stimulated FcgammaRIIa mediated by c-Cbl are positively regulated by the adaptor protein CIN85 in a PKC-dependent manner and these events contribute to the termination of FcgammaRIIa signaling. (PMID:21372129)
• the N- and C-termini are important for the structure, stability, and function of the third SH3 domain of CIN85 (PMID:21446695)
• The CIN85 was constitutively associated with Hrs, and this strengthens the hypothesis of a functional role of CIN85 in endosomal EGFR sorting. (PMID:21635887)
• Live cell imaging and co-immunoprecipitation experiments confirmed that both SLP65 and CIN85 are both required for the onset and progression phases of B-cell antigen receptor signal transduction. (PMID:21822214)
• Data show that CIN85 (c-Cbl interacting protein of 85 kDa) is constitutively associated with c-Cbl, Cbl-b, and B-cell linker in B cells. (PMID:22262777)
• this study indicates that high levels of Ruk(l)/CIN85 contribute to the conversion of breast adenocarcinoma cells into a more malignant phenotype via modulation of the Src/Akt pathway. (PMID:22791810)
• Data show that EGFR activation leads to a pronounced src-mediated tyrosine phosphorylation of CIN85 that subsequently influences EGFR ubiquitination. (PMID:22833562)
• an FRS2beta-CIN85/CD2AP-Cbl axis for downregulation of ErbB2 may regulate ErbB2 protein levels in physiological and pathological settings (PMID:23279575)
• LOX-PP interacts with CIN85 via a novel SH3-binding motif and this association reduces CIN85-promoted invasion by breast cancer cells. (PMID:24167568)
• Results support the model that Cbl-CIN85-endophilin complex is not required for efficient internalization of EGFR, a prototype RTK. (PMID:25449262)
• we demonstrate that SEPT9 negatively regulates EGFR degradation by preventing the association of the ubiquitin ligase Cbl with CIN85, resulting in reduced EGFR ubiquitylation (PMID:25472714)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	sh3kbp1	ENSDARG00000075853
mus_musculus	Sh3kbp1	ENSMUSG00000040990
rattus_norvegicus	Sh3kbp1	ENSRNOG00000004322
drosophila_melanogaster	cindr	FBGN0027598
caenorhabditis_elegans	cdap-2	WBGENE00021549

Paralogs (3): NOSTRIN (ENSG00000163072), CD2AP (ENSG00000198087), SH3D21 (ENSG00000214193)

Protein

Protein identifiers

SH3 domain-containing kinase-binding protein 1 — Q96B97 (reviewed: Q96B97)

Alternative names: CD2-binding protein 3, Cbl-interacting protein of 85 kDa, Human Src family kinase-binding protein 1

All UniProt accessions (25): Q96B97, A0A8V8TNL0, A0A8V8TNL8, A0A8V8TNP2, A0A8V8TNP7, A0A8V8TNS8, A0A8V8TNT5, A0A8V8TNU1, A0A8V8TNW8, A0A8V8TP27, A0A8V8TP33, A0A8V8TP39, A0A8V8TP40, A0A8V8TP63, A0A8V8TP69, A0A8V8TPM1, A0A8V8TPZ1, A0A8V8TQ02, A0A8V8TQC9, A0A8V8TQD8, A0A8V8TQF6, A0A8V8TQG3, A0A8V8TQU1, Q5JPT2, Q5JPT6

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein involved in regulating diverse signal transduction pathways. Involved in the regulation of endocytosis and lysosomal degradation of ligand-induced receptor tyrosine kinases, including EGFR and MET/hepatocyte growth factor receptor, through an association with CBL and endophilins. The association with CBL, and thus the receptor internalization, may be inhibited by an interaction with PDCD6IP and/or SPRY2. Involved in regulation of ligand-dependent endocytosis of the IgE receptor. Attenuates phosphatidylinositol 3-kinase activity by interaction with its regulatory subunit. May be involved in regulation of cell adhesion; promotes the interaction between TTK2B and PDCD6IP. May be involved in the regulation of cellular stress response via the MAPK pathways through its interaction with MAP3K4. Is involved in modulation of tumor necrosis factor mediated apoptosis. Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape and migration. Has an essential role in the stimulation of B cell activation.

Subunit / interactions. Can self-associate and form homotetramers. Interacts with CD2, F-actin capping protein, PIK3R3, GRB2, EGFR, MET, BLNK, MAP3K4, PDCD6IP, SPRY2, ARHGAP17, ARHGAP27, MAGI2, CRK, BCAR1, SOS1, ASAP1, ARAP3, HIP1R, SYNJ2, INPP5D and STAP1. Interacts with E3 ubiquitin-protein ligases CBL and CBLB, but does not interact with CBLC. Two molecules of SH3KBP1 seem to bind through their respective SH3 1 domain to one molecule of CBLB. The interaction with CBL or CBLB and EGFR is increased upon EGF stimulation. The interaction with CBL is attenuated by PDCD6IP. Interacts (via SH3 domains) with ARAP1. The interaction is independent of EGF and does not affect ARAP1 GTPase-activating activity but is involved in regulating ubiquitination and endocytic trafficking of EGFR. ARAP1 competes with CBL for binding to SH3KBP1 and prevents interaction of CBL with SH3KBP1; this is likely to regulate SH3KBP1-mediated internalization of EGFR. Interacts through its proline-rich region with the SH3 domain of endophilins SH3GL1, SH3GL2 and SH3GL3. The SH3KBP1-endophilin complex seems to associate with a complex containing the phosphorylated receptor (EGFR or MET) and phosphorylated CBL. Probably associates with ASAP1 and phosphorylated EGFR. Probably part of a complex consisting of at least SH3KBP1, ASAP1 and ARAP3. Interacts with focal adhesion kinases PTK2/FAK1 and PTK2B/PYK2, probably as a dimer. Interacts with DAB2 and probably associates with chathrin through its interaction with DAB2. Part of a complex consisting of SH3KBP1, DAB2, and clathrin heavy chain. DAB2 and clathrin dissociate from SH3KBP1 following growth factor treatment, enabling interaction with CBL. Interacts with DDN and probably associates with MAGI2 through its interaction with DDN. Interacts with the SH3 domains of SRC tyrosine-protein kinases SRC, LCK, LYN, FGR, FYN and HCK. Interacts with TRADD, BIRC2, TRAF1, TRAF2 and TNFR1, and the association with a TNFR1-associated complex upon stimulation with TNF seems to be mediated by SRC. Interacts (via SH3 domains) with SHKBP1 (via PXXXPR motifs). Interaction with CBL is abolished in the presence of SHKBP1. Interacts (via SH3 domains) with ZFP36 (via extreme C-terminal region). Interacts with MAP3K4; this interaction enhances the association with ZFP36. (Microbial infection) Interacts (via SH3 domains) with Chikungunya virus non-structural protein 3 (via C-terminus); this interaction plays a role in initiation of viral replication.

Subcellular location. Cytoplasm. Cytoskeleton. Cytoplasmic vesicle membrane. Synapse. Synaptosome. Cell junction. Focal adhesion.

Tissue specificity. Ubiquitously expressed. Also expressed in some cancer cell lines.

Post-translational modifications. Monoubiquitinated by CBL and CBLB after EGF stimulation; probably on its C-terminus.

Disease relevance. Immunodeficiency 61 (IMD61) [MIM:300310] An X-linked recessive primary immunologic disorder characterized by recurrent infections due to impaired antibody production. Affected individuals have normal numbers of circulating B and T cells, but B cells have an intrinsic defect in antibody production. Disease severity is variable and onset is in early childhood. The disease may be caused by variants affecting the gene represented in this entry.

Miscellaneous. Interacts with CBL. Interacts with CD2 cytoplasmic tail and does not interact with F-actin.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96B97-1	1	yes
Q96B97-2	2
Q96B97-3	3

RefSeq proteins (13): NP_001019837, NP_001171889, NP_001340819, NP_001340820, NP_001340821, NP_001340822, NP_001340823, NP_001340824, NP_001340826, NP_001397685, NP_001397686, NP_001397687, NP_114098* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR035770	CIN85_SH3_1	Domain
IPR035771	CIN85_SH3_2	Domain
IPR035772	CIN85_SH3_3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR050384	Endophilin_SH3RF	Family

Pfam: PF14604

UniProt features (54 total): strand 16, modified residue 10, compositionally biased region 7, helix 4, domain 3, splice variant 3, sequence conflict 3, region of interest 3, turn 2, chain 1, sequence variant 1, coiled-coil region 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
5ABS	X-RAY DIFFRACTION	1.74
2BZ8	X-RAY DIFFRACTION	2
2YDL	X-RAY DIFFRACTION	2.05
2K6D	SOLUTION NMR
2K9G	SOLUTION NMR
2N64	SOLUTION NMR
2O2O	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96B97-F1	63.30	0.32

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (10): 156, 159, 183, 230, 254, 436, 509, 511, 521, 587

Function

Pathways and Gene Ontology

Reactome pathways

26 pathways

ID	Pathway
R-HSA-182971	EGFR downregulation
R-HSA-6807004	Negative regulation of MET activity
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-8866376	Reelin signalling pathway
R-HSA-8875360	InlB-mediated entry of Listeria monocytogenes into host cell
R-HSA-9679191	Potential therapeutics for SARS
R-HSA-983695	Antigen activates B Cell Receptor (BCR) leading to generation of second messengers
R-HSA-1266738	Developmental Biology
R-HSA-1280218	Adaptive Immune System
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-168256	Immune System
R-HSA-177929	Signaling by EGFR
R-HSA-199991	Membrane Trafficking
R-HSA-422475	Axon guidance
R-HSA-5653656	Vesicle-mediated transport
R-HSA-5663205	Infectious disease
R-HSA-6806834	Signaling by MET
R-HSA-8876384	Listeria monocytogenes entry into host cells
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases
R-HSA-9675108	Nervous system development
R-HSA-9679506	SARS-CoV Infections
R-HSA-9824439	Bacterial Infection Pathways
R-HSA-9824446	Viral Infection Pathways
R-HSA-983705	Signaling by the B Cell Receptor (BCR)

MSigDB gene sets: 328 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_B_CELL_ACTIVATION, XU_GH1_AUTOCRINE_TARGETS_UP, CMYB_01, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_VESICLE_MEDIATED_TRANSPORT, TAL1ALPHAE47_01, REACTOME_MEMBRANE_TRAFFICKING, USF_C, GOBP_CELL_CELL_SIGNALING

GO Biological Process (8): endocytosis (GO:0006897), apoptotic process (GO:0006915), cytoskeleton organization (GO:0007010), actin filament organization (GO:0007015), cell-cell signaling (GO:0007267), regulation of cell shape (GO:0008360), cell migration (GO:0016477), positive regulation of B cell activation (GO:0050871)

GO Molecular Function (4): SH3 domain binding (GO:0017124), ubiquitin protein ligase binding (GO:0031625), protein binding (GO:0005515), kinase activity (GO:0016301)

GO Cellular Component (16): cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), focal adhesion (GO:0005925), postsynaptic density (GO:0014069), endocytic vesicle (GO:0030139), cytoplasmic vesicle membrane (GO:0030659), neuron projection (GO:0043005), glutamatergic synapse (GO:0098978), GABA-ergic synapse (GO:0098982), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), synapse (GO:0045202), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Signaling by Receptor Tyrosine Kinases	2
Signaling by EGFR	1
Signaling by MET	1
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
Axon guidance	1
Listeria monocytogenes entry into host cells	1
SARS-CoV Infections	1
Signaling by the B Cell Receptor (BCR)	1
Immune System	1
Vesicle-mediated transport	1
Nervous system development	1
Disease	1
Bacterial Infection Pathways	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
cytoplasmic vesicle	2
synapse	2
cell junction	2
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
organelle organization	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
cell communication	1
signaling	1
regulation of cell morphogenesis	1
regulation of biological quality	1
cell motility	1
B cell activation	1
regulation of B cell activation	1
positive regulation of lymphocyte activation	1
protein domain specific binding	1
ubiquitin-like protein ligase binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
membrane	1
cell periphery	1
anchoring junction	1
cell-substrate junction	1
asymmetric synapse	1
postsynaptic specialization	1
vesicle membrane	1
plasma membrane bounded cell projection	1
intracellular vesicle	1

Protein interactions and networks

STRING

1828 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SH3KBP1	CBL	P22681	996
SH3KBP1	BLNK	Q8WV28	930
SH3KBP1	MET	P08581	785
SH3KBP1	SH3GLB2	Q9NR46	734
SH3KBP1	ARAP3	Q8WWN8	708
SH3KBP1	ARHGAP27	Q6ZUM4	687
SH3KBP1	EGFR	P00533	661
SH3KBP1	BIN1	O00499	650
SH3KBP1	SNX9	Q9Y5X1	632
SH3KBP1	CTTN	Q14247	619
SH3KBP1	EGF	P01133	617
SH3KBP1	ARAP1	Q96P48	610
SH3KBP1	SHC1	P29353	584
SH3KBP1	HCK	P08631	576
SH3KBP1	SH3GLB1	Q9Y371	570

IntAct

328 interactions, top by confidence:

A	B	Type	Score
CBL	SH3KBP1	psi-mi:“MI:0915”(physical association)	0.980
SH3KBP1	CBL	psi-mi:“MI:0915”(physical association)	0.980
SH3KBP1	CBL	psi-mi:“MI:0914”(association)	0.980
CBLB	SH3KBP1	psi-mi:“MI:0915”(physical association)	0.960
CBLB	SH3KBP1	psi-mi:“MI:0407”(direct interaction)	0.960
SH3KBP1	CBLB	psi-mi:“MI:0407”(direct interaction)	0.960
ASAP1	SH3KBP1	psi-mi:“MI:0915”(physical association)	0.880
PALS1	LIN7A	psi-mi:“MI:0914”(association)	0.870
SGF29	NDC80	psi-mi:“MI:0914”(association)	0.840
TP63	TP73	psi-mi:“MI:0914”(association)	0.770
Dab2	SH3KBP1	psi-mi:“MI:0915”(physical association)	0.670
SH3KBP1	Dab2	psi-mi:“MI:0915”(physical association)	0.670
SH3KBP1	Dab2	psi-mi:“MI:0914”(association)	0.670
SH3KBP1	USP27X	psi-mi:“MI:0914”(association)	0.640
CAPZB	CNOT1	psi-mi:“MI:0914”(association)	0.640
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.640

BioGRID (669): SH3KBP1 (Affinity Capture-Western), SH3KBP1 (Two-hybrid), SH3KBP1 (Two-hybrid), SH3KBP1 (Two-hybrid), SH3KBP1 (Two-hybrid), SH3KBP1 (Two-hybrid), ZBTB7B (Two-hybrid), PNMA5 (Two-hybrid), SH3KBP1 (Affinity Capture-RNA), SH3KBP1 (Affinity Capture-RNA), SH3KBP1 (Affinity Capture-RNA), MAP3K4 (Affinity Capture-Western), SH3KBP1 (Biochemical Activity), SH3KBP1 (Co-crystal Structure), SH3KBP1 (Affinity Capture-MS)

ESM2 similar proteins: A0JMZ1, A1L209, A1L2F3, A1L3I5, A2AWT3, A4FUE7, A6QQM4, O82171, O94519, P97868, Q08AZ1, Q14CW9, Q1W1G1, Q22122, Q2HJG4, Q2YDJ0, Q32KN7, Q5EAW4, Q5PPV5, Q5REC0, Q5TFG8, Q5ZMS6, Q618K0, Q62920, Q64GL0, Q66HC1, Q6DGN6, Q6NRP6, Q6P1U3, Q6V5K9, Q7SXT7, Q7Z6E9, Q801E2, Q8BJH1, Q8CI51, Q8H100, Q8IMP6, Q8IYB5, Q8R550, Q91W18

Diamond homologs: A0JNJ1, A1CEK6, A1DFN5, A2QW93, A4RF61, A6QLK6, A7A261, F1LRS8, O35179, O35964, O43307, O74749, O75791, O75886, O88811, O89100, O93436, P02549, P07751, P09215, P09216, P10830, P13395, P16054, P16086, P16546, P23298, P24723, P28867, P29355, P32793, P34885, P38753, P43603, P53281, P62993, P62994, P70297, P87379, P97306

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SH3KBP1	up-regulates	CBL	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 130 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of signaling by CBL	5	28.9×	2e-04
RHOF GTPase cycle	6	18.1×	2e-04
RHOQ GTPase cycle	5	10.5×	6e-03
CDC42 GTPase cycle	11	9.2×	2e-05
RAC3 GTPase cycle	6	8.3×	6e-03
RAC1 GTPase cycle	10	7.1×	2e-04
RHOA GTPase cycle	7	6.1×	7e-03
Signaling by Rho GTPases	10	4.0×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	6	22.8×	3e-04
cell surface receptor protein tyrosine kinase signaling pathway	7	11.0×	2e-03
regulation of small GTPase mediated signal transduction	7	9.1×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

549 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	183
Likely benign	168
Benign	19

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
626219	NC_000023.10:g.19667630_19886572del	Pathogenic
997059	GRCh37/hg19 Xp22.13-22.12(chrX:19183657-20215858)	Pathogenic

SpliceAI

5577 predictions. Top by Δscore:

Variant	Effect	Δscore
X:19541923:A:AC	donor_gain	1.0000
X:19541924:C:CA	donor_gain	1.0000
X:19541924:CT:C	donor_gain	1.0000
X:19541924:CTT:C	donor_gain	1.0000
X:19545920:A:AC	donor_gain	1.0000
X:19545921:C:CC	donor_gain	1.0000
X:19546048:TGA:T	acceptor_gain	1.0000
X:19546051:C:CC	acceptor_gain	1.0000
X:19547262:T:TA	donor_gain	1.0000
X:19549972:A:AC	donor_gain	1.0000
X:19549973:C:CC	donor_gain	1.0000
X:19550084:C:CC	acceptor_gain	1.0000
X:19569097:A:AC	donor_gain	1.0000
X:19569098:C:CC	donor_gain	1.0000
X:19569099:T:TA	donor_loss	1.0000
X:19569100:CACC:C	donor_loss	1.0000
X:19569101:A:AC	donor_gain	1.0000
X:19569101:A:AG	donor_loss	1.0000
X:19569102:C:CC	donor_gain	1.0000
X:19588811:CAT:C	acceptor_gain	1.0000
X:19588813:T:C	acceptor_gain	1.0000
X:19588813:T:TC	acceptor_gain	1.0000
X:19588817:T:C	acceptor_gain	1.0000
X:19588817:T:TC	acceptor_gain	1.0000
X:19592144:GTGCC:G	acceptor_loss	1.0000
X:19592145:TGCCT:T	acceptor_loss	1.0000
X:19592148:C:CC	acceptor_gain	1.0000
X:19592148:CTAGG:C	acceptor_loss	1.0000
X:19592149:T:G	acceptor_loss	1.0000
X:19607932:ACTT:A	donor_loss	1.0000

AlphaMissense

4343 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:19537730:C:G	R648P	1.000
X:19550019:T:A	R483S	1.000
X:19550019:T:G	R483S	1.000
X:19550020:C:G	R483T	1.000
X:19607977:G:C	F322L	1.000
X:19607977:G:T	F322L	1.000
X:19607978:A:G	F322S	1.000
X:19607979:A:G	F322L	1.000
X:19607980:G:C	N321K	1.000
X:19607980:G:T	N321K	1.000
X:19607987:G:C	P319R	1.000
X:19607987:G:T	P319H	1.000
X:19607988:G:A	P319S	1.000
X:19607988:G:T	P319T	1.000
X:19607990:A:G	F318S	1.000
X:19607996:C:T	G316D	1.000
X:19607997:C:G	G316R	1.000
X:19608017:C:T	G309E	1.000
X:19608018:C:G	G309R	1.000
X:19608018:C:T	G309R	1.000
X:19608025:C:A	W306C	1.000
X:19608025:C:G	W306C	1.000
X:19608026:C:G	W306S	1.000
X:19608027:A:G	W306R	1.000
X:19608027:A:T	W306R	1.000
X:19608029:C:T	G305D	1.000
X:19608030:C:G	G305R	1.000
X:19631880:A:T	V294D	1.000
X:19631904:A:G	L286S	1.000
X:19631907:T:A	E285V	1.000

dbSNP variants (sampled 300 via entrez): RS1000005192 (X:19839958 T>G), RS1000022578 (X:19661773 T>C), RS1000034956 (X:19886211 G>A), RS1000037922 (X:19802714 C>G), RS1000043304 (X:19720695 CTT>C), RS1000053230 (X:19703162 C>A), RS1000104892 (X:19568624 A>G), RS1000131567 (X:19777660 G>A), RS1000144912 (X:19641226 G>A), RS1000149171 (X:19647094 T>C), RS1000171479 (X:19736334 G>A), RS1000175015 (X:19848750 G>A,C), RS1000179322 (X:19710559 A>G), RS1000180650 (X:19647552 C>A), RS1000189648 (X:19609042 A>C,T)

Disease associations

OMIM: gene MIM:300374 | disease phenotypes: MIM:300310, MIM:601086

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 61	Moderate	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
immunodeficiency 61	Limited	XL

Mondo (3): immunodeficiency 61 (MONDO:0010296), laterality defects, autosomal dominant (MONDO:0010991), renal agenesis, unilateral (MONDO:0019636)

Orphanet (5): Non-syndromic agammaglobulinemia (Orphanet:229717), X-linked agammaglobulinemia (Orphanet:47), X-linked common variable immunodeficiency phenotype due to SH3KBP1 deficiency (Orphanet:696945), Visceral heterotaxy (Orphanet:450), Renal agenesis, unilateral (Orphanet:93100)

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000403	Recurrent otitis media
HP:0001419	X-linked recessive inheritance
HP:0001513	Obesity
HP:0002205	Recurrent respiratory infections
HP:0002718	Recurrent bacterial infections
HP:0002850	Decreased circulating total IgM
HP:0003593	Infantile onset
HP:0007018	Attention deficit hyperactivity disorder
HP:0008348	Decreased circulating IgG2 concentration
HP:0011108	Recurrent sinusitis
HP:0032138	Decreased circulating IgG4 concentration

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002402_508	Platelet count	8.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C538057	Agammaglobulinemia, X-linked, type 2 (supp.)
C563391	Laterality Defects, Autosomal Dominant (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

77 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	5
bisphenol A	decreases expression, decreases methylation, affects cotreatment	3
trichostatin A	affects cotreatment, increases expression	3
Particulate Matter	increases abundance, increases expression, decreases expression, affects cotreatment	3
entinostat	increases expression, affects cotreatment	2
(+)-JQ1 compound	decreases expression	2
Panobinostat	increases expression, affects cotreatment	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Lead	affects splicing, decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression, increases methylation	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
1-Methyl-4-phenylpyridinium	affects expression, increases expression	2
Sodium Selenite	increases expression	2
Cadmium Chloride	increases expression, decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
glycidyl methacrylate	increases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
tobacco tar	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	decreases expression, affects cotreatment	1
aflatoxin B2	decreases methylation	1
cupric chloride	increases expression	1
coumarin	increases phosphorylation	1
hydroquinone	increases expression	1
1-nitropyrene	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E1MH	HyCyte Ramos KO-hSH3KBP1	Cancer cell line	Male

Clinical trials (associated diseases)

1 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01831141	Not specified	UNKNOWN	Long Term Outcome of Congenital Solitary Kidney