Trask phosphorylation defines the reverse mode of a phosphotyrosine signaling switch that underlies cell anchorage state &lt;link href="file

Spassov, Danislav S.; Wong, Ching Hang; Moasser, Mark M.

doi:10.4161/cc.10.8.15343

Cited by 9 publications

(10 citation statements)

References 54 publications

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“…These authors proposed that CDCP1 signaling and focal adhesion signaling function in opposition during changes in cell attachment (29,44). This is consistent with our observations that suggest that this opposition defines an SFK-mediated switch.…”

Section: Discussionsupporting

confidence: 92%

Cellular Settings Mediating Src Substrate Switching between Focal Adhesion Kinase Tyrosine 861 and CUB-domain-containing protein 1 (CDCP1) Tyrosine 734

Wortmann

Christensen

et al. 2011

Journal of Biological Chemistry

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Background: Focal adhesion kinase (FAK) and CUB-domain-containing protein 1 (CDCP1) are Src family kinase (SFK) substrates. Results: SFK switching between FAK-Tyr-861 and CDCP1-Tyr-734 is induced by increased CDCP1 expression and changes in cell attachment. Conclusion: SFK switching between FAK and CDCP1 may be relevant to malignant transformation. Significance: Targeting of this switch may be a rational approach to treat diseases such as cancer.

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Section: Discussionsupporting

confidence: 92%

Cellular Settings Mediating Src Substrate Switching between Focal Adhesion Kinase Tyrosine 861 and CUB-domain-containing protein 1 (CDCP1) Tyrosine 734

Wortmann

Christensen

et al. 2011

Journal of Biological Chemistry

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“…These novel in vivo findings are in apparent contrast with some recent in vitro findings linking overexpression of CDCP1 with Src activation (Liu et al , 2011), but support previously shown dependence of in vitro phosphorylation of CDCP1 on activated Src (Alvares et al , 2008; Benes et al , 2005; Brown et al , 2004; Miyazawa et al , 2010; Spassov et al , 2011a; Spassov et al , 2011b). In addition, we have highlighted that Src-mediated signaling in vivo should be initiated not later that 24 hr after cell inoculations to promote CDCP1-dependent colonization, independently providing another support for an early signal cascade induced by CDCP1 cleavage.…”

Section: Discussionsupporting

confidence: 56%

Blocking of CDCP1 cleavage in vivo prevents Akt-dependent survival and inhibits metastatic colonization through PARP1-mediated apoptosis of cancer cells

et al. 2011

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The CUB domain-containing protein 1 (CDCP1) is a transmembrane molecule that recently has been implicated in cancer progression. In this study we have established a novel mechanism for initiation of CDCP1-mediated signaling in vivo and demonstrated that specific 135→70 kDa processing of cell surface CDCP1 by extracellular serine proteases is a prerequisite for CDCP1-dependent survival of cancer cells during metastasis. The in vivo cleavage of CDCP1 triggers a survival program involving recruitment of Src and PKCδ, Src-mediated phosphorylation of cell surface-retained 70 kDa CDCP1, activation of Akt, and suppression of PARP1-induced apoptosis. We demonstrate in vivo that phosphorylated Src, PKCδ and Akt, all constitute activated elements of a CDCP1 signaling axis during tissue colonization of tumor cells. Preventing the in vivo cleavage of CDCP1 with unique anti-CDCP1 antibodies, serine protease inhibitors or genetic modulation of the cleavage site in the CDCP1 molecule completely abrogated survival signaling associated with the 70 kDa CDCP1 and induced PARP1 cleavage and PARP1-mediated apoptosis, ultimately resulting in substantial inhibition of tissue colonization by tumor cells. The lack of CDCP1 cleavage in the lung tissue of plasminogen knockout mice along with a coordinated reduction in tumor cell survival in a lung retention model and importantly the rescue of both by in vivo supplied plasmin, indicated that plasmin is the crucial serine protease executing in vivo cleavage of cell surface CDCP1 during early stages of lung colonization. Together, our findings indicate that in vivo blocking of CDCP1 cleavage upstream of CDCP1-induced pro-survival signaling provides a potential mechanism for therapeutic intervention into metastatic disease.

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“…In cultured cells we found that Trask undergoes phosphorylation by Src kinases immediately upon the loss of anchorage, and accounts for the majority of cellular phosphotyrosine content in the unanchored state in many cells, and remains phosphorylated until anchorage is restored (13, 15). When phosphorylated, Trask functions to negatively regulate cell adhesion.…”

Section: Introductionmentioning

confidence: 96%

“…P-Trask interferes with most integrin complexes and adhesion to most matrix ligands, resulting in the inhibition of physical cell-matrix adhesion and consequently the disruption of focal adhesions and focal adhesion signaling through FAK, 130Cas, paxillin, and other focal adhesion proteins (16). Importantly the phosphorylation of Trask and the phosphorylation of focal adhesion proteins, including FAK, occur in exclusion of eachother, defining a phosphotyrosine switch that underlies cell anchorage state (15, 16). …”

Section: Introductionmentioning

confidence: 99%

Trask Loss Enhances Tumorigenic Growth by Liberating Integrin Signaling and Growth Factor Receptor Cross-Talk in Unanchored Cells

Spassov

Wong

et al. 2013

Cancer Research

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The cell surface glycoprotein Trask/CDCP1 is phosphorylated during anchorage loss in epithelial cells where it inhibits integrin clustering, outside-in signaling and cell adhesion. Its role in cancer has been difficult to understand, because of the lack of a discernible pattern in its various alterations in cancer cells. To address this issue, we generated mice lacking Trask function. Mammary tumors driven by the PyMT oncogene and skin tumors driven by the SmoM2 oncogene arose with accelerated kinetics in Trask deficient mice, establishing a tumor suppressing function for this gene. Mechanistic investigations in mammary tumor cell lines derived from wildtype or Trask-deficient mice revealed a derepression of integrin signaling and an enhancement of integrin-growth factor receptor crosstalk, specifically in unanchored cell states. A similar restrictive link between anchorage and growth in untransformed epithelial cells was observed and disrupted by elimination of Trask. Together our results establish a tumor suppressing function in Trask that restricts epithelial cell growth to the anchored state.

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Trask phosphorylation defines the reverse mode of a phosphotyrosine signaling switch that underlies cell anchorage state <link href="file

Cited by 9 publications

References 54 publications

Cellular Settings Mediating Src Substrate Switching between Focal Adhesion Kinase Tyrosine 861 and CUB-domain-containing protein 1 (CDCP1) Tyrosine 734

Cellular Settings Mediating Src Substrate Switching between Focal Adhesion Kinase Tyrosine 861 and CUB-domain-containing protein 1 (CDCP1) Tyrosine 734

Blocking of CDCP1 cleavage in vivo prevents Akt-dependent survival and inhibits metastatic colonization through PARP1-mediated apoptosis of cancer cells

Trask Loss Enhances Tumorigenic Growth by Liberating Integrin Signaling and Growth Factor Receptor Cross-Talk in Unanchored Cells

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