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

Abstract

Src family nonreceptor tyrosine kinases are an integral component of the signal transduction apparatus employed by growth factor receptor tyrosine kinases. As such, their role in cellular growth control and malignant transformation has been the subject of intensive investigation. In contrast, classical G-protein-coupled receptor (GPCR) signaling involves activation of second messenger-regulated serine/threonine kinases or ion channels, and is primarily involved in neurotransmission and the short-term regulation of intermediary metabolism. Over the past decade, this strictly dichotomous model of transmembrane signaling has been challenged by the discovery that GPCRs also exert control over cellular growth, proliferation, and differentiation, and do so by stimulating tyrosine phosphorylation cascades. Several mechanisms, from the direct association of Src family kinases with GPCRs or receptor-associated proteins, to the transactivation of receptor tyrosine kinases and focal adhesion complexes by G-protein-mediated signals, permit GPCRs to activate Src family kinases. Conversely, Src activity plays a central role in controlling GPCR trafficking and effects on cell proliferation and cytoskeletal rearrangement. It is now clear that GPCRs and Src family kinases do not belong to separate, exclusive clubs. Rather, these strange bedfellows are intimately involved in multilayered forms of crosstalk that influence a host of cellular processes.

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Abbreviations

CSK:

C-terminal Src kinase

EGF:

epidermal growth factor

ERK:

extracellular signal-regulated kinase

FAK:

focal adhesion kinase

GEF:

guanine nucleotide exchange factor

GPCR:

G-protein-coupled receptor

G protein:

heterotrimeric guanine nucleotide-binding protein

GRK:

G-protein-coupled receptor kinase

HB-EGF:

heparin-binding EGF

JNK:

c-Jun N-terminal kinase

LPA:

lysophosphatidic acid

MAP:

mitogen-activated protein

MMP:

matrix metalloprotease

PDGF:

platelet-derived growth factor

PKA:

protein kinase A

PKC:

protein kinase C

TGFα:

transforming growth factor α

SH2:

Src homology domain 2

SH3:

Src homology domain 3

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Acknowledgements

The research in the authors' laboratory is supported by grants from the National Institutes of Health DK55524, DK58283, and DK64353 (to LML).

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Luttrell, D., Luttrell, L. Not so strange bedfellows: G-protein-coupled receptors and Src family kinases. Oncogene 23, 7969–7978 (2004). https://doi.org/10.1038/sj.onc.1208162

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