Activated CDC42 kinase 1

Definition:

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.

References:

[1]. Noriko Yokoyama, et al. Purification and enzyme activity of ACK1. Methods Enzymol. 2006;406:250-60. [Content Brief]

[2]. Kiran Mahajan, et al. Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PLoS One. 2010 Mar 19;5(3):e9646. [Content Brief]

[3]. Katarzyna Modzelewska, et al. Ack1 mediates Cdc42-dependent cell migration and signaling to p130Cas. J Biol Chem. 2006 Dec 8;281(49):37527-35. [Content Brief]

[4]. Lene Melsaether Grøvdal, et al. Dysregulation of Ack1 inhibits down-regulation of the EGF receptor. Exp Cell Res. 2008 Apr 1;314(6):1292-300. [Content Brief]

[5]. Victoria Prieto-Echagüe, et al. Cancer-associated mutations activate the nonreceptor tyrosine kinase Ack1. J Biol Chem. 2010 Apr 2;285(14):10605-15. [Content Brief]

[6]. Y Liu, et al. Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases. Oncogene. 2010 Jun 3;29(22):3208-16. [Content Brief]

[7]. Edward Htun van der Horst, et al. Metastatic properties and genomic amplification of the tyrosine kinase gene ACK1. Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15901-6. [Content Brief]

[8]. J Kato, et al. Activation of the guanine nucleotide exchange factor Dbl following ACK1-dependent tyrosine phosphorylation. Biochem Biophys Res Commun. 2000 Feb 5;268(1):141-7. [Content Brief]

[9]. M Teo, et al. The tyrosine kinase ACK1 associates with clathrin-coated vesicles through a binding motif shared by arrestin and other adaptors. J Biol Chem. 2001 May 25;276(21):18392-8. [Content Brief]

[10]. Noriko Yokoyama, et al. Phosphorylation of WASP by the Cdc42-associated kinase ACK1: dual hydroxyamino acid specificity in a tyrosine kinase. J Biol Chem. 2005 Dec 23;280(51):42219-26. [Content Brief]

[11]. Lin Pao-Chun, et al. Cytoplasmic ACK1 interaction with multiple receptor tyrosine kinases is mediated by Grb2: an analysis of ACK1 effects on Axl signaling. J Biol Chem. 2009 Dec 11;284(50):34954-63. [Content Brief]

[12]. Jillian Howlin, et al. TNK2 preserves epidermal growth factor receptor expression on the cell surface and enhances migration and invasion of human breast cancer cells. Breast Cancer Res. 2008;10(2):R36. [Content Brief]

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