Signaling by PTK6

Stable Identifier
Homo sapiens
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PTK6 (BRK) is an oncogenic non-receptor tyrosine kinase that functions downstream of ERBB2 (HER2) (Xiang et al. 2008, Peng et al. 2015) and other receptor tyrosine kinases, such as EGFR (Kamalati et al. 1996) and MET (Castro and Lange 2010). Since ERBB2 forms heterodimers with EGFR and since MET can heterodimerize with both ERBB2 and EGFR (Tanizaki et al. 2011), it is not clear if MET and EGFR activate PTK6 directly or act through ERBB2. Levels of PTK6 increase under hypoxic conditions (Regan Anderson et al. 2013, Pires et al. 2014). The kinase activity of PTK6 is negatively regulated by PTPN1 phosphatase (Fan et al. 2013) and SRMS kinase (Fan et al. 2015), as well as the STAT3 target SOCS3 (Gao et al. 2012).

PTK6 activates STAT3-mediated transcription (Ikeda et al. 2009, Ikeda et al. 2010) and may also activate STAT5-mediated transcription (Ikeda et al. 2011). PTK6 promotes cell motility and migration by regulating the activity of RHO GTPases RAC1 (Chen et al. 2004) and RHOA (Shen et al. 2008), and possibly by affecting motility-related kinesins (Lukong and Richard 2008). PTK6 crosstalks with AKT1 (Zhang et al. 2005, Zheng et al. 2010) and RAS signaling cascades (Shen et al. 2008, Ono et al. 2014) and may be involved in MAPK7 (ERK5) activation (Ostrander et al. 2007, Zheng et al. 2012). PTK6 enhances EGFR signaling by inhibiting EGFR down-regulation (Kang et al. 2010, Li et al. 2012, Kang and Lee 2013). PTK6 may also enhance signaling by IGF1R (Fan et al. 2013) and ERBB3 (Kamalati et al. 2000).

PTK6 promotes cell cycle progression by phosphorylating and inactivating CDK inhibitor CDKN1B (p27) (Patel et al. 2015).

PTK6 activity is upregulated in osteopontin (OPN or SPP1)-mediated signaling, leading to increased VEGF expression via PTK6/NF-kappaB/ATF4 signaling path. PTK6 may therefore play a role in VEGF-dependent tumor angiogenesis (Chakraborty et al. 2008).

PTK6 binds and phosphorylates several nuclear RNA-binding proteins, including SAM68 family members (KHDRSB1, KHDRSB2 and KHDRSB3) (Derry et al. 2000, Haegebarth et al. 2004, Lukong et al. 2005) and SFPQ (PSF) (Lukong et al. 2009). The biological role of PTK6 in RNA processing is not known.

For a review of PTK6 function, please refer to Goel and Lukong 2015.

Literature References
PubMed ID Title Journal Year
15539407 Regulated association of protein kinase B/Akt with breast tumor kinase

Lange, CA, Olsen, A, Faivre, EJ, Ostrander, JH, Fitzsimmons, D, Zhang, P

J. Biol. Chem. 2005
20606012 Protein tyrosine kinase 6 directly phosphorylates AKT and promotes AKT activation in response to epidermal growth factor

Zheng, Y, Wang, Z, Peng, M, Tyner, AL, Asara, JM

Mol. Cell. Biol. 2010
8940083 Brk, a breast tumor-derived non-receptor protein-tyrosine kinase, sensitizes mammary epithelial cells to epidermal growth factor

Gusterson, BA, Jackson, LE, Crompton, MR, Kamalati, T, Jolin, HE, Dean, CJ, Page, MJ, Barker, KT, Mitchell, PJ

J. Biol. Chem. 1996
23352614 PTK6 promotes degradation of c-Cbl through PTK6-mediated phosphorylation

Lee, ST, Kang, SA

Biochem. Biophys. Res. Commun. 2013
21205088 Involvement of STAP-2 in Brk-mediated phosphorylation and activation of STAT5 in breast cancer cells

Matsuda, T, Mizushima, A, Nanbo, A, Ikeda, O, Sekine, Y, Muromoto, R, Yamamoto, C, Yoshimura, A, Oritani, K

Cancer Sci. 2011
18719096 Brk is coamplified with ErbB2 to promote proliferation in breast cancer

Muthuswamy, SK, Xiang, B, Lakshmi, B, Yu, M, Miller, WT, Krasnitz, A, Hicks, J, Qiu, H, Chatti, K

Proc. Natl. Acad. Sci. U.S.A. 2008
20929863 Interactions of STAP-2 with Brk and STAT3 participate in cell growth of human breast cancer cells

Miyasaka, Y, Matsuda, T, Mizushima, A, Nanbo, A, Ikeda, O, Sekine, Y, Nakasuji, M, Muromoto, R, Yamamoto, C, Yoshimura, A, Oritani, K

J. Biol. Chem. 2010
19439179 BRK phosphorylates PSF promoting its cytoplasmic localization and cell cycle arrest

Huot, ME, Lukong, KE, Richard, S

Cell. Signal. 2009
25733683 Brk/Protein tyrosine kinase 6 phosphorylates p27KIP1, regulating the activity of cyclin D-cyclin-dependent kinase 4

Wagner, R, Patel, P, Asbach, B, Blain, SW, Coltoff, A, Shteyn, E, Gomez, C, Bhuyan, S, Tyner, AL

Mol. Cell. Biol. 2015
17483331 Breast tumor kinase (protein tyrosine kinase 6) regulates heregulin-induced activation of ERK5 and p38 MAP kinases in breast cancer cells

Lange, CA, Ostrander, JH, Kleer, CG, Lofgren, K, Daniel, AR

Cancer Res. 2007
22547065 Suppressor of cytokine signaling 3 inhibits breast tumor kinase activation of STAT3

Reich, NC, Cimica, V, Gao, Y

J. Biol. Chem. 2012
20687930 Breast tumor kinase and extracellular signal-regulated kinase 5 mediate Met receptor signaling to cell migration in breast cancer cells

Lange, CA, Castro, NE

Breast Cancer Res. 2010
20554524 PTK6 inhibits down-regulation of EGF receptor through phosphorylation of ARAP1

Randazzo, PA, Lee, ES, Lee, ST, Yoon, HY, Kang, SA

J. Biol. Chem. 2010
25999240 Tracing the footprints of the breast cancer oncogene BRK - Past till present

Goel, RK, Lukong, KE

Biochim. Biophys. Acta 2015
18077133 Breast tumor kinase BRK requires kinesin-2 subunit KAP3A in modulation of cell migration

Lukong, KE, Richard, S

Cell. Signal. 2008
18829532 Breast tumor kinase phosphorylates p190RhoGAP to regulate rho and ras and promote breast carcinoma growth, migration, and invasion

Kuo, ML, Li, FY, Settleman, J, Shen, CH, Chen, HY, Chang, CC, Chen, RH, Lin, MS

Cancer Res. 2008
11114724 Expression of the BRK tyrosine kinase in mammary epithelial cells enhances the coupling of EGF signalling to PI 3-kinase and Akt, via erbB3 phosphorylation

Fry, MJ, Crompton, MR, Kamalati, T, Jolin, HE

Oncogene 2000
22231447 Brk/PTK6 sustains activated EGFR signaling through inhibiting EGFR degradation and transactivating EGFR

Fan, Z, Li, X, Lu, Y, Liang, K, Albarracin, C, Hsu, JM, Mills, GB, Hung, MC

Oncogene 2012
19393627 STAP-2 is phosphorylated at tyrosine-250 by Brk and modulates Brk-mediated STAT3 activation

Miyasaka, Y, Matsuda, T, Mizushima, A, Nanbo, A, Ikeda, O, Sekine, Y, Muromoto, R, Yoshimura, A

Biochem. Biophys. Res. Commun. 2009
18172307 Osteopontin promotes vascular endothelial growth factor-dependent breast tumor growth and angiogenesis via autocrine and paracrine mechanisms

Chakraborty, G, Jain, S, Kundu, GC

Cancer Res. 2008
22084245 Protein-tyrosine kinase 6 promotes peripheral adhesion complex formation and cell migration by phosphorylating p130 CRK-associated substrate

Zheng, Y, Tyner, AL, Asara, JM

J. Biol. Chem. 2012
25897081 Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase

Fan, G, Yang, M, Aleem, S, Miller, WT, Tonks, NK

J. Biol. Chem. 2015
15471878 The nuclear tyrosine kinase BRK/Sik phosphorylates and inhibits the RNA-binding activities of the Sam68-like mammalian proteins SLM-1 and SLM-2

Richard, S, Bie, W, Derry, JJ, Haegebarth, A, Heap, D, Tyner, AL

J. Biol. Chem. 2004
23814047 Protein-tyrosine phosphatase 1B antagonized signaling by insulin-like growth factor-1 receptor and kinase BRK/PTK6 in ovarian cancer cells

Fan, G, Tonks, NK, Lin, G, Lucito, R

J. Biol. Chem. 2013
16179349 Tyrosine phosphorylation of sam68 by breast tumor kinase regulates intranuclear localization and cell cycle progression

Richard, S, Lukong, KE, Larocque, D, Tyner, AL

J. Biol. Chem. 2005
21847121 Differential roles of trans-phosphorylated EGFR, HER2, HER3, and RET as heterodimerisation partners of MET in lung cancer with MET amplification

Nakagawa, K, Tanizaki, J, Okamoto, I, Sakai, K

Br. J. Cancer 2011
25019382 HIF-1α-independent hypoxia-induced rapid PTK6 stabilization is associated with increased motility and invasion

Span, PN, Pires, IM, Hammond, EM, Eccles, SA, Blokland, NJ, Poujade, FA, Senra, JM, Broos, AW, Harvey, AJ

Cancer Biol. Ther. 2014
26247733 Protein tyrosine kinase 6 promotes ERBB2-induced mammary gland tumorigenesis in the mouse

Peng, M, Tyner, AL, Ball-Kell, SM

Cell Death Dis 2015
10913193 Sik (BRK) phosphorylates Sam68 in the nucleus and negatively regulates its RNA binding ability

Tyner, AL, Richard, S, Chen, T, Ye, X, Valderrama Carvajal, H, Cochrane, AW, Derry, JJ, Vasioukhin, V

Mol. Cell. Biol. 2000
24788754 PTK6 promotes cancer migration and invasion in pancreatic cancer cells dependent on ERK signaling

Ito, H, Basson, MD, Ono, H

PLoS ONE 2014
23928995 Breast tumor kinase (Brk/PTK6) is a mediator of hypoxia-associated breast cancer progression

Wenger, RH, Regan Anderson, TM, Lange, CA, Schörg, A, Seagroves, TN, Lofgren, KA, Girard, BJ, Peacock, DL, Hoogewijs, D, Hubbard, GK, Daniel, AR

Cancer Res. 2013
15572663 Brk activates rac1 and promotes cell migration and invasion by phosphorylating paxillin

Huang, YP, Tsai, YT, Shen, CH, Lin, FC, Chen, HY, Chen, RH

Mol. Cell. Biol. 2004
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