Focal Adhesion Kinase-Related Proline-Rich Tyrosine Kinase 2 and Focal Adhesion Kinase Are Co-Overexpressed in Early-Stage and Invasive ErbB-2-Positive Breast Cancer and Cooperate for Breast Cancer Cell Tumorigenesis and Invasiveness

Behmoaram, Emy; Bijian, Krikor; Shi, Jie; Xu, Yingjie; Darnel, Andrew D.; Bismar, Tarek A.; Alaoui‐Jamali, Moulay A.

doi:10.2353/ajpath.2008.080292

Cited by 60 publications

(49 citation statements)

References 62 publications

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“…The nonreceptor tyrosine kinase has been reported to play a role in dysregulation of various cellular processes in tumor cells, and may be interesting for immunotherapy as potential tumor-associated antigen. [47][48][49][50][51] This is supported by the finding that antibodies against PTK2B have been observed in 3 of 19 patients with CML who responded to CD4 ϩ DLI. 52 Because PTK2B is an intracellular protein, antibodies against PTK2B are not expected to contribute directly to the elimination of tumor cells in vivo.…”

Section: Discussionsupporting

confidence: 70%

Identification of 4 new HLA-DR–restricted minor histocompatibility antigens as hematopoietic targets in antitumor immunity

Stumpf

Meijden

Bergen

et al. 2009

Blood

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Section: Discussionsupporting

confidence: 70%

Identification of 4 new HLA-DR–restricted minor histocompatibility antigens as hematopoietic targets in antitumor immunity

Stumpf

Meijden

Bergen

et al. 2009

Blood

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“…Therefore, data presented in this paper add to the mounting evidence for an important connection between Pyk2 and the EGFR. This generates interest in Pyk2 as a therapeutic target for not only wound healing but also EGFR-related pathologies, such as certain cancers and cardiac hypertrophy (41,(63)(64)(65)(66)(67).…”

Section: Discussionmentioning

confidence: 99%

Pyk2 Activation Triggers Epidermal Growth Factor Receptor Signaling and Cell Motility after Wounding Sheets of Epithelial Cells

Block

Tolino

Klarlund

2010

Journal of Biological Chemistry

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Activation of the epidermal growth factor receptor (EGFR) is a key signaling event that promotes cells to move and cover wounds in many epithelia. We have previously shown that wounding activates the EGFR through activation of the Src family kinases (SFKs), which induce proteolytic shedding of epidermal growth factor-like ligands from the cell surface. A major goal in wound healing research is to identify early signals that promote motility, and here we examined the hypothesis that members of the focal adhesion kinase family are upstream activators of the SFKs after wounding. We found that focal adhesion kinase is not activated by wounding but that a different family member, Pyk2 (PTK2B/RAFTK/CAK␤), is activated rapidly and potently. Pyk2 interaction with c-Src is increased after wounding, as determined by co-immunoprecipitation experiments. Disruption of Pyk2 signaling either by small interfering RNA or by expression of a dominant negative mutant led to inhibition of wound-induced activation of the SFKs and the EGFR, and conversely, overexpression of wild-type Pyk2 stimulated SFK and EGFR kinase activities in cells. In wound healing studies, Pyk2 small interfering RNA or dominant negative inhibited cell migration. These results show that activation of Pyk2 is an early signal that promotes wound healing by stimulating the SFK/ EGFR signaling pathway.Wounding induces profound changes in adjacent epithelial cells, which include rearrangement of the actin cytoskeleton, internalization of cell junction proteins, and redistribution of membrane phospholipids (1-4), and they subsequently acquire a phenotype that allows them to migrate rapidly (5, 6). Activation of the epidermal growth factor receptor (EGFR) 2 tyrosine kinase (7, 8) is an obligatory signaling event that stimulates a multitude of downstream effectors to induce these changes in many epithelia, including the gut, airway, epidermis, and cornea (9 -14). Understanding the molecular mechanisms of wound-induced EGFR activation is central to understanding how epithelia acquire a motile phenotype.The proximal event for activation of the EGFR is proteolytic release of transmembrane ligands, such as heparin-binding EGF-like growth factor, by a mechanism that resembles transactivation of the EGFR by G-protein coupled receptors (15)(16)(17)(18)(19)(20). Recent data suggest that the Src family kinases (SFKs) control EGFR ligand shedding after wounding (5, 21). The SFKs are ubiquitously expressed non-receptor tyrosine kinases that regulate cytoskeletal dynamics, cell/matrix interactions, and transduction of extracellular signals (22). The SFKs contain Src homology 2 and 3 domains that bind to consensus phosphotyrosine and proline-rich domains, respectively, which can lead to activation by loss of inhibitory intramolecular interactions (23).We have recently found that SFKs and the EGFR are activated rapidly in cells within 250 m of the wound edge (5). In addition, extracellular ATP is released from cells and can induce activation of the EGFR further from the wounds. How...

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“…Several investigational drugs, including small molecule kinase inhibitors against FA and its homologue Pyk2 (Roberts et al, 2008), are at the stage of early clinical trials and may prove more efficient modulators of FA turnover and hence can prevent the progression of invasive cancers to metastases. This is particularly important as many of the FA proteins, such as ErbB receptors, are overexpressed in invasive cancers (Behmoaram et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Regulation of focal adhesion turnover by ErbB signalling in invasive breast cancer cells

Benlimame

Shi

et al. 2009

Br J Cancer

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A crucial early event by which cancer cells switch from localised to invasive phenotype is initiated by the acquisition of autonomous motile properties; a process driven by dynamic assembly and disassembly of multiple focal adhesion (FA) proteins, which mediate cell -matrix attachments, extracellular matrix degradation, and serve as traction sites for cell motility. We have reported previously that cancer cell invasion induced by overexpression of members of the ErbB tyrosine kinase receptors, including ErbB2, is dependent on FA signalling through FA kinase (FAK). Here, we show that ErbB2 receptor signalling regulates FA turnover, and cell migration and invasion through the Src -FAK pathway. Inhibition of the Src -FAK signalling in The ability of invasive tumour cells to invade surrounding tissue structures at primary sites requires tumour cell capacity to become motile and invasive. This process involves a series of cellular events, which includes formation and extension of protrusions in response to chemotactic signals, formation of stable cell focal adhesion (FA) -matrix attachment near the leading edge of the protrusions, and movement of the cell body forward aided by the release and retraction of the FAs at the trailing edge of the cell. Therefore, FAs are established as key regulators of cell motility and cell invasion since they can act as signalling centres and provide robust anchors to the extracellular matrix (ECM), which represent traction points for the generation of cell tension and motility.Several protein kinases and phosphatases appear to be central to the regulation of adhesion turnover and stability, including the FA kinase (FAK). We have reported that ErbB2-induced cell invasion is dependent on FAK signalling (Benlimame et al, 2005). Focal adhesion kinase is a key multifunctional adaptor and signalling molecule that has been shown to play a role in FA formation and turnover and is required for cell motility and cell invasion (Ilic et al, 1995;Sieg et al, 2000). In motile cells, FAK along with other partners of the FA network is recruited to membrane cell protrusion following integrin engagement and/or receptor activation, where it becomes autophosphorylated at tyrosine Y397. Src is then recruited through its SH2 domain to the phosphorylated FAK, and both enzymes subsequently phosphorylate additional FAK tyrosine residues in the catalytic and C-terminal domains creating additional docking sites for SH2-containing proteins (Schaller et al, 1994;Calalb et al, 1995;Parsons et al, 2000). Similar to FAK, Src also regulates FA dynamics and both FAK-and Src-deficient fibroblasts have motility defects and stable FAs attributed to defective FA turnover required for cell locomotion.In this study, we established a functional role for ErbB signalling in the regulation of FA turnover in invasive cells through the Src -FAK pathway, and provided a novel mechanism for the anti-ErB2 antibody Herceptin in inhibiting FA turnover and preventing the early stage cancer invasion.

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Focal Adhesion Kinase-Related Proline-Rich Tyrosine Kinase 2 and Focal Adhesion Kinase Are Co-Overexpressed in Early-Stage and Invasive ErbB-2-Positive Breast Cancer and Cooperate for Breast Cancer Cell Tumorigenesis and Invasiveness

Cited by 60 publications

References 62 publications

Identification of 4 new HLA-DR–restricted minor histocompatibility antigens as hematopoietic targets in antitumor immunity

Identification of 4 new HLA-DR–restricted minor histocompatibility antigens as hematopoietic targets in antitumor immunity

Pyk2 Activation Triggers Epidermal Growth Factor Receptor Signaling and Cell Motility after Wounding Sheets of Epithelial Cells

Regulation of focal adhesion turnover by ErbB signalling in invasive breast cancer cells

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