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

Kamalati, Tahereh; Jolin, Helen E.; Fry, Michael; Crompton, M. R.

doi:10.1038/sj.onc.1203931

Cited by 109 publications

(136 citation statements)

References 27 publications

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“…26 The mysterious nuclear and nucleolar activities of ERBB3 76,78,79 must be unraveled. Further study is needed of the involvement of non-NRG, non-ERBB regulators of ERBB3, such as CDK5, [122][123][124] BRK, 125 SRC, 126 and MET. 120 The fascinating and widely expressed ERBB3 effector EBP1 has thus far been examined mainly in mammary and prostate cells; [154][155][156][157][158][159][160][161][162][163][164] may it be important also in other cancers where ERBB3 is clearly a player, such as lung and melanoma?…”

Section: Discussionmentioning

confidence: 99%

“…It also coimmunoprecipitated with ERBB3 when both were overexpressed in human embryonic kidney cells. 126 Direct phosphorylation of ERBB3 by BRK was postulated but has not yet been directly demonstrated.…”

Section: Erbb3 Interacting Proteins: Activation Signaling and Regulamentioning

confidence: 99%

“…These results indicate, for ovarian cancer cells, a central role for ERBB3 in activation of ERBB4, and suggest that ERBB3 itself is activated by a path other than the other ERBB receptors, either its own very weak kinase activity, or by recruitment of some other kinase known to increase its activation, such as PTK6 125 or c-SRC. 126 Another intriguing observation was the presence of truncated ERBB3 transcripts of 1.6, 1.7, 2.1 and 2.3 kb in ovarian carcinoma cells lines. 23 When cloned into fibroblasts, three of these made truncated proteins, including several that were secreted and one that was retained intracellularly.…”

Section: Ovarian Cancermentioning

confidence: 99%

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The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

Section: Erbb3 Interacting Proteins: Activation Signaling and Regulamentioning

confidence: 99%

Section: Ovarian Cancermentioning

confidence: 99%

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The ERBB3 receptor in cancer and cancer gene therapy

2008

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“…Overexpression of PTK6-mRNA positively correlates with hormone receptor status (Zhao et al, 2003) and HER2/NEU expression (Born et al, 2005) in breast cancer specimens. Several in vitro studies of PTK6 point to a possible role in modulating signal transduction of receptor tyrosine kinases (RTKs): PTK6 expression increases HER3 phosphorylation and Akt activation (Kamalati et al, 2000;Zhang et al, 2005), sensitises cells to epidermal growth factor (EGF) (Kamalati et al, 1996), which activates PTK6 (Kamalati et al, 2000;Chen et al, 2004), and influences the apoptotic pathway (Haegebarth et al, 2005). There are, however, several unanswered questions with regard to the structure, activity, and regulation of PTK6.…”

mentioning

confidence: 99%

PTK (protein tyrosine kinase)-6 and HER2 and 4, but not HER1 and 3 predict long-term survival in breast carcinomas

et al. 2007

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The HER receptors are of therapeutic and prognostic significance in breast cancer, and their function is modulated by cytoplasmic tyrosine kinases like PTK6 (brk). We performed a retrospective study on archival breast cancer samples from patients with long follow-up and compared the protein expression between individual HERs and between HERs and the PTK6. Univariate and multivariate analyses were used to study the prognostic value of parameters. Metastases-free survival of patients for longer than 240 months was inversely associated (Pp0.05) with nodal status, tumour size, and oestrogen receptor status, but was also directly associated with high protein expression levels of HER4 and PTK6 in Kaplan -Meier analysis. In multivariate analysis for metastases-free survival of 4240 months, the stepwise selected parameters were tumour size (relative risk 3.1), PTK6 expression (0.4), and number of positive lymph nodes (1.2). Furthermore, we demonstrated a timedependence of the prognostic value attributed to the parameters. The HER receptors (HER2,4), but not PTK6, were independent prognostic markers for metastases-free survival at 60 months, whereas at 240 months PTK6 is the strongest prognostic marker. We demonstrate that PTK6 is a prognostic marker of metastases-free survival in breast cancer, and is independent of the classical morphological and molecular markers of lymph node involvement, tumour size, and HER2 status.

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“…It phosphorylates ARAP1, which results sequentially in inhibition of EGFR internalization, increased duration of EGF/EGFR signaling, and increased oncogenic capacity (Kang et al, 2010). Importantly, over-expression of BRK sensitizes human mammary epithelial cells to EGF and/or heregulin stimuli, and increases anchorage-independent growth (Kamalati et al, 1996(Kamalati et al, , 2000, while down-regulation of BRK also influences EGF-and heregulin-induced cell proliferation. These observations suggest that BRK is involved in signaling induced by members of the EGFR family (Ostrander et al, 2007).…”

Section: Substrates Interacting Proteins and Activationmentioning

confidence: 99%