Not so strange bedfellows: G-protein-coupled receptors and Src family kinases

Luttrell, Deirdre K.; Luttrell, Louis M.

doi:10.1038/sj.onc.1208162

Cited by 199 publications

(185 citation statements)

References 104 publications

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“…The Src family of nonreceptor tyrosine kinases, which includes Src, Lyn, Fyn, Yes, Lck, Blk, and Hyc, are important mediators of multiple physiological processes, such as cell proliferation, survival, and adhesion (24). Members of the Src nonreceptor tyrosine kinase family have also been shown to be important for GPCR agonist-induced Erk1͞2 activation via EGFR (9).…”

Section: Resultsmentioning

confidence: 99%

erbB2 is required for G protein-coupled receptor signaling in the heart

Negro

Brar

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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erbB2͞Her2, a ligandless receptor kinase, has pleiotropic effects on mammalian development and human disease. The absence of erbB2 signaling in cardiac myocytes results in dilated cardiomyopathy in mice, resembling the cardiotoxic effects observed in a subset of breast cancer patients treated with the anti-Her2 antibody herceptin. Emerging evidence suggests that erbB2 is pivotal for integrating signaling networks involving multiple classes of extracellular signals. However, its role in G protein-coupled receptor (GPCR) signaling remains undefined. Because the activation of the MAPK pathway through GPCR signaling is important for cardiac homeostasis, we investigated whether erbB2 is required for GPCR-mediated MAPK signaling in wild-type and heart-specific erbB2 mutant mice. Here we demonstrate that erbB2, but not EGF receptor, is essential for MAPK activation induced by multiple GPCR agonists in cardiac myocytes. erbB2 is immunocomplexed with a GPCR in vivo and is transactivated after ligand treatment in vitro. Coexpression of erbB2 with GPCRs in heterologous cells results in ligand-dependent complex formation and MAPK activation. Furthermore, MAPK activation and cardiac contractility are markedly impaired in heart-specific erbB2 mutants infused with a GPCR agonist. These results reveal an essential mechanism requiring erbB2 as a coreceptor for GPCR signaling in the heart. The obligatory role of erbB2 in GPCR-dependent signaling may also be important in other cellular systems.MAPK ͉ cardiac myocytes ͉ erbB2 mutants

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Section: Resultsmentioning

confidence: 99%

erbB2 is required for G protein-coupled receptor signaling in the heart

Negro

Brar

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Although intermediates in the pathway, we do not know whether SFKs directly phosphorylate these receptor tyrosine kinases or if the effect is indirect. Similarly, although it is parsimonious to posit that the neuroprotective action of blocking SFKs is attributable to their ability to decrease TrkB activation, the plethora of SFK substrates (in particular MAPK) raise other possibilities (Murray et al, 1998;Runden et al, 1998;Grewal et al, 1999;Ishikawa et al, 2000;Kaplan and Miller, 2000;Kim et al, 2003;Bromann et al, 2004;Choi et al, 2004;Luttrell and Luttrell, 2004). Regardless of its precise mechanism of action, increases in SFK activity can adversely affect neuronal health (or exacerbate toxic insult, i.e., A␤ peptides) and inhibition of SFK activity can protect neurons from insult (Lambert et al, 1998;Chin et al, 2004Chin et al, , 2005Lennmyr et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Protecting Motor Neurons from Toxic Insult by Antagonism of Adenosine A2a and Trk Receptors

Mojsilovic-Petrovic¹,

Jeong²,

Crocker³

et al. 2006

J. Neurosci.

133

125

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The death of motor neurons in amyotrophic lateral sclerosis (ALS) is thought to result from the interaction of a variety of factors including excitotoxicity, accumulation of toxic proteins, and abnormal axonal transport. Previously, we found that the susceptibility of motor neurons to excitotoxic insults can be limited by inhibiting signals evoked by brain-derived neurotrophic factor (BDNF) activation of the receptor tyrosine kinase B (TrkB). Here we show that this can be achieved by direct kinase inhibition or by blockade of a transactivation pathway that uses adenosine A2a receptors and src-family kinases (SFKs). Downstream signaling cascades (such as mitogen-activated protein kinase and phosphatidylinositol-3 kinase) are inhibited by these blockers. In addition to protecting motor neurons from excitotoxic insult, these agents also prevent toxicity that follows from the expression of mutant proteins (G85R superoxide dismutase 1; G59S p150 glued ) that cause familial motor neuron disease. TrkB, adenosine A2a receptors, and SFKs associate into complexes in lipid raft and nonlipid raft membranes and the signaling from lipids rafts may be particularly important because their disruption by cholesterol depletion blocks the ability of BDNF to render motor neurons vulnerable to insult. The neuroprotective versatility of Trk antagonism suggests that it may have broad utility in the treatment of ALS patients.

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“…In general, G-protein -coupled receptors can transactivate HER family members either by ectodomain shedding of membrane-bound HER family receptor ligands by members of the ADAM (a Disintegrin and metalloprotease) family of proteases (5) or by intracellular phosphorylation of HER family members involving Src kinase (6). In breast cancer cells, CXCL12/CXCR4 interaction activates HER2 in a Src kinasedependent mechanism (7).…”

Section: Introductionmentioning

confidence: 99%

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

Chinni

Yamamoto

Dong

et al. 2008

Molecular Cancer Research

120

102

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Chemokines and their receptors function in migration and homing of cells to target tissues. Recent evidence suggests that cancer cells use a chemokine receptor axis for metastasis formation at secondary sites. Previously, we showed that binding of the chemokine CXCL12 to its receptor CXCR4 mediated signaling events resulting in matrix metalloproteinase-9 expression in prostate cancer bone metastasis. A variety of methods, including lipid raft isolation, stable overexpression of CXCR4, cellular adhesion, invasion assays, and the severe combined immunodeficient -human bone tumor growth model were used. We found that (a) CXCR4 and HER2 coexist in lipid rafts of prostate cancer cells; (b) the CXCL12/CXCR4 axis results in transactivation of the HER2 receptor in lipid rafts of prostate cancer cells; (c) Src kinase mediates CXCL12/CXCR4 transactivation of HER2 in prostate cancer cells; (d) a pan-HER inhibitor desensitizes CXCR4-induced transactivation and subsequent matrix metalloproteinase-9 secretion and invasion; (e) lipid raft -disrupting agents inhibited raft-associated CXCL12/CXCR4 transactivation of the HER2 and cellular invasion; (f) overexpression of CXCR4 in prostate cancer cells leads to increased HER2 phosphorylation and migratory properties of prostate cancer cells; and (g) CXCR4 overexpression enhances bone tumor growth and osteolysis. These data suggest that lipid rafts on the cell membrane are the key site for CXCL12/CXCR4 -induced HER2 receptor transactivation. This transactivation contributes to enhanced invasive signals and metastatic growth in the bone microenvironment.

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Not so strange bedfellows: G-protein-coupled receptors and Src family kinases

Cited by 199 publications

References 104 publications

erbB2 is required for G protein-coupled receptor signaling in the heart

erbB2 is required for G protein-coupled receptor signaling in the heart

Protecting Motor Neurons from Toxic Insult by Antagonism of Adenosine A2a and Trk Receptors

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

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