Mechanisms of HGF/Met Signaling to Brk and Sam68 in Breast Cancer Progression

Abstract

Signal transduction pathways downstream of receptor tyrosine kinases (RTKs) are often deregulated during oncogenesis, tumor progression, and metastasis. In particular, the peptide growth factor hormone, hepatocyte growth factor (HGF), and its specific receptor, Met tyrosine kinase, regulate cancer cell migration, thereby conferring an aggressive phenotype (Nakamura et al., J Clin Invest 106 (12):1511–1519, 2000; Huh et al., Proc Natl Acad Sci U S A 101:4477–4482, 2004). Additionally, overexpression of Met is associated with enhanced invasiveness of breast cancer cells (Edakuni et al., Pathol Int 51(3):172–178, 2001; Jin et al., Cancer 79(4):749–760, 1997; Tuck et al., Am J Pathol 148(1):225–232, 1996). Here, we review the regulation of recently identified novel downstream mediators of HGF/Met signaling, Breast tumor kinase (Brk/PTK6), and Src-associated substrate during mitosis of 68 kDa (Sam68), and discuss their relevance to mechanisms of breast cancer progression.

Protein-tyrosine Phosphatase 1B Antagonized Signaling by Insulin-like Growth Factor-1 Receptor and Kinase BRK/PTK6 in Ovarian Cancer Cells*

“…HER2 (40,48), and complex formation between the BRK and HER2 proteins, which promotes HER2 signaling in breast cancer (31). The effects of BRK are not restricted to the EGFR family; for example, it is also activated downstream of MET, which is associated with increased invasiveness of breast cancer cell lines (49). Nevertheless, despite all of this progress, very little is known about the impact of protein phosphatases on the function of BRK.…”

PTK6 (protein tyrosine kinase 6)

“…PTK6 binds and phosphorylates IGF-1R and promotes anchorage independent growth via interactions with IRS-4 and IGF1R (Qiu et al, 2005;Irie et al, 2010). PTK6 has also been shown to mediate Met receptor signaling, although a direct interaction has not been demonstrated (Locatelli et al, 2012). PTK6 stabilizes EGFR expression by phosphorylating ARAP1 (Arf-GAP, Rho-GAP, ankyrin repeat, and pleckstrin homology domain-containing protein 1) (Kang et al, 2010); interaction with EGFR mediates PTK6 phosphorylation of paxillin (Chen et al, 2004) and p190RhoGAP (Shen et al, 2008) in breast cancer cells as well as AKT in breast (Zhang et al, 2005) and prostate cancer cell lines to promote proliferation, invasion, and migration.…”

Identification of Novel HIF1A Target Genes That Regulate Tumor Progression and Metastasis

“…Although an improved understanding of Brk signaling in breast cancer is rapidly emerging [308,[310][311][312], the mechanisms by which Brk is aberrantly expressed in the majority of breast cancers remains undefined. We have identified cellular microenvironmental stressors, including hypoxia, to be major cues that result in increased Brk expression in both normal and neoplastic mammary epithelial cells.…”

“…Our previous studies have elucidated downstream mediators of Brk signaling that include stress-activated protein kinases (p38 MAPK and ERK5) as well as their substrates MEF2 and Sam68 [310][311][312]. Breast cancer cells maintain high soluble and growth factor receptor tyrosine kinase activities relative to untransformed cells [340]; these pathways may act as inputs to increased Brk and ERK5 activities [308,314].…”

“…Many Brk substrates, both cytoplasmic and nuclear, have important functions in cancer, including signal transducer and activator of transcription (STAT) molecules, Akt, and Sam68 (reviewed in [308]). Brk is activated downstream of ErbB family receptors and Met receptors and is required for EGF-, heregulin-, and hepatocyte growth factor (HGF)-enhanced cell migration [310][311][312]. Although Brk and ErbB2 have distinct gene loci, they are coamplified in some breast cancers [313], potentially leading to enhanced MAPK signaling and cell proliferation.…”