TNK2

This gene encodes a tyrosine kinase that binds Cdc42Hs in its GTP-bound form and inhibits both the intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activity of Cdc42Hs. This binding is mediated by a unique sequence of 47 amino acids C-terminal to an SH3 domain. The protein may be involved in a regulatory mechanism that sustains the GTP-bound active form of Cdc42Hs and which is directly linked to a tyrosine phosphorylation signal transduction pathway. Several alternatively spliced transcript variants have been identified from this gene, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]

Full Name

TNK2 Gene(Protein Coding) Tyrosine Kinase Non Receptor 2

Function

Non-receptor tyrosine-protein and serine/threonine-protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation. Transduces extracellular signals to cytosolic and nuclear effectors. Phosphorylates AKT1, AR, MCF2, WASL and WWOX. Implicated in trafficking and clathrin-mediated endocytosis through binding to epidermal growth factor receptor (EGFR) and clathrin. Binds to both poly- and mono-ubiquitin and regulates ligand-induced degradation of EGFR, thereby contributing to the accumulation of EGFR at the limiting membrane of early endosomes. Downstream effector of CDC42 which mediates CDC42-dependent cell migration via phosphorylation of BCAR1. May be involved both in adult synaptic function and plasticity and in brain development. Activates AKT1 by phosphorylating it on 'Tyr-176'. Phosphorylates AR on 'Tyr-267' and 'Tyr-363' thereby promoting its recruitment to androgen-responsive enhancers (AREs). Phosphorylates WWOX on 'Tyr-287'. Phosphorylates MCF2, thereby enhancing its activity as a guanine nucleotide exchange factor (GEF) toward Rho family proteins. Contributes to the control of AXL receptor levels. Confers metastatic properties on cancer cells and promotes tumor growth by negatively regulating tumor suppressor such as WWOX and positively regulating pro-survival factors such as AKT1 and AR. Phosphorylates WASP (PubMed:20110370).

Biological Process

Cell differentiationManual Assertion Based On ExperimentIBA:GO_Central
Cell surface receptor signaling pathwayManual Assertion Based On ExperimentTAS:UniProtKB
EndocytosisIEA:UniProtKB-KW
Innate immune responseManual Assertion Based On ExperimentIBA:GO_Central
PhosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of peptidyl-tyrosine phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Regulation of clathrin-dependent endocytosisManual Assertion Based On ExperimentIDA:UniProtKB
Small GTPase mediated signal transductionManual Assertion Based On ExperimentTAS:ProtInc
Transmembrane receptor protein tyrosine kinase signaling pathwayManual Assertion Based On ExperimentIBA:GO_Central

Cellular Location

Cell membrane
Nucleus
Endosome
Cell junction, adherens junction
Cytoplasmic vesicle membrane
Cytoplasmic vesicle, clathrin-coated vesicle
Membrane, clathrin-coated pit
Cytoplasm, perinuclear region
Cytoplasm, cytosol
The Tyr-284 phosphorylated form is found both in the membrane and nucleus (By similarity).
Co-localizes with EGFR on endosomes (PubMed:20333297).
Nuclear translocation is CDC42-dependent (By similarity).
Detected in long filamentous cytosolic structures where it co-localizes with CTPS1 (By similarity).

PTM

Autophosphorylation regulates kinase activity. Phosphorylation on Tyr-518 is required for interaction with SRC and is observed during association with clathrin-coated pits.
Polyubiquitinated by NEDD4 and NEDD4L. Degradation can be induced by EGF and is lysosome-dependent (By similarity).