Receptor Protein-Tyrosine Kinases and Their Signal Transduction Pathways

Geer, Peter van der; Hunter, Tony; Lindberg, Richard A.

doi:10.1146/annurev.cb.10.110194.001343

Cited by 1,181 publications

(679 citation statements)

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“…Most tyrosine kinase receptors (RTK) were shown to activate the Ras-dependent pathway through Grb2 and/or Shc adapters (McCormick, 1993;Van der Geer et al, 1994). Consistent with this, Axl cytoplasmic domain was shown to bind Grb2 protein (Braunger et al, 1997;Fridell et al, 1995) and Gas6 addition to serum starved cells induced a signi®cant activation of Shc (Goruppi et al, 1996).…”

Section: Ras Blocking Antibodies Ablate Gas6-induced Mitogenesismentioning

confidence: 92%

Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras

et al. 1999

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Section: Ras Blocking Antibodies Ablate Gas6-induced Mitogenesismentioning

confidence: 92%

Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras

et al. 1999

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“…Overexpression or mutation at the transmembrane domain of ErbB2 leads to autophosphorylation of tyrosine residues in its carboxy-terminal domain. The phosphorylated tyrosine residues then function as docking sites for ErbB2 downstream signaling molecules (Van der Geer et al, 1994;Holbro et al, 2003). However, the overall picture of how ErbB2 exerts its function through its downstream signaling pathways and the signaling events responsible for ErbB2-enhanced cancer metastasis are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Upregulation and activation of PKCα by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKCα and Src inhibitors

Tan

Sun

et al. 2006

Oncogene

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Although ErbB2 is known to enhance breast cancer metastasis, the signaling events responsible for this remain elusive. a-Isozyme of protein kinase C (PKCa), which is involved in cancer development and progression, has been suggested to be activated by ErbB2 without direct evidence. In addition, the roles of PKCa in ErbB2-mediated cancer cell malignancy have not been clearly identified. In this study, we investigated whether ErbB2 can activate PKCa and determined what role PKCa plays in ErbB2-mediated breast cancer cell invasion. We expressed wild-type and mutant ErbB2 with altered signaling capacities in MDA-MB-435 breast cancer cells and revealed that overexpression or activation of ErbB2 in MDA-MB-435 cells upregulated and activated PKCa and that downregulation of ErbB2 by small-interfering RNA decreased the expression and activity of PKCa in BT474 breast cancer cells. These in vitro results were supported by data from breast cancer patient samples. In 150 breast cancer tumor samples, ErbB2-overexpressing tumors showed significantly higher positive rates of PKCa membrane immunohistochemistry staining than that of ErbB2-low-expressing tumors. Mechanistically, we found that PKCa is co-immunoprecipitated with Src and PKCa expression and activity can be decreased by Src inhibitor PP2 and by the expression of a dominantnegative mutant of Src. Moreover, ErbB2-mediated upregulation of urokinase-type plasminogen activator receptor (uPAR) is reduced by either the PKCa inhibitor Go6976 or the Src inhibitor PP2, and the combination of Go6976 with PP2 is superior to either agent alone in suppressing uPAR expression and cell invasion. These results demonstrate that PKCa is critical for ErbB2-mediated cancer cell invasion and provide valuable insights for current and future PKCa and Src inhibitor clinical trials.

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“…Signaling by RTKs involves ligand binding followed by receptor dimerization and phosphorylation on tyrosine residues (reviewed in Van der Geer and Lindberg, 1994). This autophosphorylation creates high a nity binding sites for speci®c intracellular signaling molecules which contain motifs that recognize phosphotyrosine, namely SH2 (src homology 2) and PTB (phosphotyrosine binding) domains (reviewed in Pawson, 1995).…”

Section: Introductionmentioning

confidence: 99%

The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R

1998

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Tek/Tie2 is an endothelial cell-speci®c receptor tyrosine kinase that has been shown to play a role in vascular development of the mouse. Targeted mutagenesis of both Tek and its agonistic ligand, Angiopoietin-1, result in embryonic lethality, demonstrating that the signal transduction pathway(s) mediated by this receptor are crucial for normal embryonic development. In an attempt to identify downstream signaling partners of the Tek receptor, we have used the yeast two-hybrid system to identify phosphotyrosine-dependent interactions. Using this approach, we have identi®ed a novel docking molecule called Dok-R, which has sequence and structural homology to p62 dok and IRS-3. Mapping of the phosphotyrosine-interaction domain within Dok-R shows that Dok-R interacts with Tek through a PTB domain. Dok-R is coexpressed with Tek in a number of endothelial cell lines. We show that coexpression of Dok-R with activated Tek results in tyrosine phosphorylation of Dok-R and that rasGAP and Nck coimmunoprecipitate with phosphorylated Dok-R. Furthermore, Dok-R is constitutively bound to Crk presumably through the proline rich tail of Dok-R. The cloning of Dok-R represents the ®rst downstream substrate of the activated Tek receptor, and suggests that Tek can signal through a multitude of pathways.

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Receptor Protein-Tyrosine Kinases and Their Signal Transduction Pathways

Cited by 1,181 publications

References 0 publications

Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras

Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras

Upregulation and activation of PKCα by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKCα and Src inhibitors

The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R

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