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  • Original Paper
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Sustained recruitment of phospholipase C-γ to Gab1 is required for HGF-induced branching tubulogenesis

Oncogene volume 19, pages 1509–1518 (2000)Cite this article

Abstract

A distinctive property of Hepatocyte Growth Factor (HGF) is its ability to induce differentiation of tubular structures from epithelial and endothelial cells (branching tubulogenesis). The HGF receptor directly activates PI3 kinase, Ras and STAT signalling pathways and phosphorylates the adaptator GRB2 Associated Binder-1 (Gab1). Gab1 is also phosphorylated in response to Epidermal Growth Factor (EGF) but is unable to induce tubule formation. Comparison of 32P-peptide maps of Gab1 from EGF- versus HGF-treated cells, demonstrates that the same sites are phosphorylated in vivo. However, while both EGF and HGF induce rapid tyrosine phosphorylation of Gab1 with a peak at 15 min, the phosphorylation persists for over 1 h, only in response to HGF. Nine tyrosines are phosphorylated by both receptors. Three of them (Y307, Y373, Y407) bind phospholipase C-γ (PLC-γ). Interestingly, the overexpression of a Gab1 mutant unable to bind PLC-γ (Gab1 Y307/373/407F) did not alter HGF-stimulated cell scattering, only partially reduced the growth stimulation but completely abolished HGF-mediated tubulogenesis. It is concluded that sustained recruitment of PLCγ to Gab1 plays an important role in branching tubulogenesis.

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Abbreviations

DAG:

diacylglycerol

EGF:

epidermal growth factor

Gab1:

GRB2 associated binder-1

GRB-2:

growth factor receptor-bound protein 2

GST:

glutathione S-transferase

HGF:

hepatocyte growth factor

IP3:

inosotol-1,4,5 triphosphare

NGF:

nervous growth factor

p85:

the 85 kDa regulatory subunit of PI 3 kinase

PDGF:

platelet-derived growth factor

PI 3 kinase:

phosphoinositide 3 kinase

PLC:

phospholipase C

SH2:

Src homology 2

SHC:

Src homology/collagen

SHPTP:

SH2 containing Phosphotyrosine phosphatase

STAT:

signal transducer and activator of the transcription

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Acknowledgements

We are grateful to Dr W Birchmeier for mouse Gab1 cDNA, Dr PP Di Fiore for GST-PLCγ fusion proteins and Dr T Miki for pCEV29.1 plasmid. The excellent technical assistance of L Palmas, R Albano and G Petruccelli is gratefully acknowledged. We thank Antonella Cignetto for secretarial help and Elaine Wright for editing the manuscript. This work was supported by BIOMED EC grant no. BMH4-98-3852 to PM Comoglio. P Gual and TA Williams are supported by Marie Curie TMR fellowships.

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Authors and Affiliations

  1. Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Str. Prov. 142, Km 3.95, 10060 Candiolo, Italy

    Philippe Gual, Silvia Giordano, Tracy A Williams & Paolo M Comoglio

  2. Institut National de la Santé et de la Recherche (INSERM) U145, Faculté de Médecine, avenue de Valombrose 06107, Nice cédex 2, France

    Stephane Rocchi & Emmanuel Van Obberghen

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Gual, P., Giordano, S., Williams, T. et al. Sustained recruitment of phospholipase C-γ to Gab1 is required for HGF-induced branching tubulogenesis. Oncogene 19, 1509–1518 (2000). https://doi.org/10.1038/sj.onc.1203514

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