Trask is a recently described transmembrane substrate of Src kinases whose expression and phosphorylation has been correlated
with the biology of some cancers. Little is known about the molecular functions of Trask, although its phosphorylation has
been associated with cell adhesion. We have studied the effects of Trask phosphorylation on cell adhesion, integrin activation,
clustering, and focal adhesion signaling. The small hairpin RNA (shRNA) knockdown of Trask results in increased cell adhesiveness
and a failure to properly inactivate focal adhesion signaling, even in the unanchored state. On the contrary, the experimentally
induced phosphorylation of Trask results in the inhibition of cell adhesion and inhibition of focal adhesion signaling. This
is mediated through the inhibition of integrin clustering without affecting integrin affinity state or ligand binding activity.
Furthermore, Trask signaling and focal adhesion signaling inactivate each other and signal in exclusion with each other, constituting
a switch that underlies cell anchorage state. These data provide considerable insight into how Trask functions to regulate
cell adhesion and reveal a novel pathway through which Src kinases can oppose integrin-mediated cell adhesion.
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"Since metastatic spread of cancer decreases the quality of life and ultimately leads to death, it is critical to understand the mechanisms that AR uses to drive metastasis. Src plays a well-known role in regulating cell migration and invasion through phosphorylation of many substrates including p130Cas, Shc, FAK, p190RhoGAP, paxillin, and CDCP1 [144,145] . Clinically, Src is implicated in driving bone metastasis. "
[Show abstract][Hide abstract]ABSTRACT: The androgen receptor (AR) remains the major oncogenic driver of prostate cancer, as evidenced by the efficacy of androgen deprivation therapy (ADT) in naïve patients, and the continued effectiveness of second generation ADTs in castration resistant disease. However, current ADTs are limited to interfering with AR ligand binding, either through suppression of androgen production or the use of competitive antagonists. Recent studies demonstrate 1) the expression of constitutively active AR splice variants that no longer depend on androgen, and 2) the ability of AR to signal in the cytoplasm independently of its transcriptional activity (non-genomic); thus highlighting the need to consider other ways to target AR. Herein, we review canonical AR signaling, but focus on AR non-genomic signaling, some of its downstream targets and how these effectors contribute to prostate cancer cell behavior. The goals of this review are to 1) re-highlight the continued importance of AR in prostate cancer as the primary driver, 2) discuss the limitations in continuing to use ligand binding as the sole targeting mechanism, 3) discuss the implications of AR non-genomic signaling in cancer progression and therapeutic resistance, and 4) address the need to consider non-genomic AR signaling mechanisms and pathways as a viable targeting strategy in combination with current therapies.
Full-text · Article · Jan 2016 · Cellular Signalling
"The residual focus forming capacity of the single Y734 mutant supports its prominent role that has been described earlier [11,30] but is not sufficient for efficient transformation and implicates additional pathways for CDCP1 signaling. Recently, Spassov et al.  showed that phosphorylation of the major tyrosine sites of CDCP1 inhibited cell adhesion and focal adhesion signaling by preventing integrin clustering. Also in their system, overexpression of a YDF mutant lacking three intracellular Tyr residues was no longer able to inhibit cell adhesion. "
[Show abstract][Hide abstract]ABSTRACT: Cub domain containing protein 1 (CDCP1) is strongly expressed in tumors derived from lung, colon, ovary, or kidney. It is a membrane protein that is phosphorylated and then bound by Src family kinases. Although expression and phosphorylation of CDCP1 have been investigated in many tumor cell lines, the CDCP1 features responsible for transformation have not been fully evaluated. This is in part due to the lack of an experimental system in which cellular transformation depends on expression of exogenous CDCP1 and Src. Here we use retrovirus mediated co-overexpression of c-Src and CDCP1 to induce focus formation of NIH3T3 cells. Employing different mutants of CDCP1 we show that for a full transformation capacity, the intact amino- and carboxy-termini of CDCP1 are essential. Mutation of any of the core intracellular tyrosine residues (Y734, Y743, or Y762) abolished transformation, and mutation of a palmitoylation motif (C689,690G) strongly reduced it. Src kinase binding to CDCP1 was not required since Src with a defective SH2 domain generated even more CDCP1 dependent foci whereas Src myristoylation was necessary. Taken together, the focus formation assay allowed us to define structural requirements of CDCP1/Src dependent transformation and to characterize the interaction of CDCP1 and Src.
"They observed that integrin clusterings in the periphery of the cell occur within minutes, starts about after 3 minutes. There are also many recent studies on integrin clustering, such as by        . "
[Show abstract][Hide abstract]ABSTRACT: When invading the tissue, malignant tumour cells (i.e. cancer cells) need to detach from neighbouring cells, degrade the basement membrane, and migrate through the extracellular matrix. These processes require loss of cell-cell adhesion and enhancement of cell-matrix adhesion. In this paper we present a mathematical model of an intracellular pathway for the interactions between a cancer cell and the extracellular matrix. Cancer cells use similar mechanisms as with normal cells for their interactions with the extracellular matrix. We develop a model of cell-matrix adhesion that accounts for reactions between the cell surface receptor integrins, the matrix glycoprotein fibronectin, and the actin filaments in the cytoskeleton. Each represents components for an intermediate compartment, the extracellular compartment, and the intracellular compartment, respectively. Binding of fibronectin with integrins triggers a clustering of protein complexes, which then activates and phosphorylates regulatory proteins that are involved in actin reorganisation causing actin polymerization and stress fibre assembly. Rearrangement of actin filaments with integrin/fibronectin complexes near adhesion sites and interaction with fibrillar fibronectin produces
the force necessary for cell migration, accounting for cell-matrix adhesion.
Full-text · Article · Jan 2012 · Mathematical Modelling of Natural Phenomena