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Molecular and Cellular Biology, May 2000, p. 3482-3496, Vol. 20, No. 10
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Enhanced Transformation by a Plasma Membrane-Associated Met Oncoprotein: Activation of a Phosphoinositide 3'-Kinase-Dependent Autocrine Loop Involving Hyaluronic Acid and CD44

Darren M. Kamikura,1,dagger Hanane Khoury,2 Christiane Maroun,1 Monica A. Naujokas,1 and Morag Park1,2,3,*

Molecular Oncology Group, Departments of Medicine,1 Oncology,3 and Biochemistry,2 Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada H3A-1A1

Received 3 May 1999/Returned for modification 21 July 1999/Accepted 31 January 2000

A Met-hepatocyte growth factor receptor oncoprotein, Tpr-Met, generated by chromosomal rearrangement, fuses a protein dimerization motif with the cytoplasmic domain of the Met receptor, producing a cytosolic, constitutively activated tyrosine kinase. Although both the Met receptor and the Tpr-Met oncoprotein associate with the same substrates, activating mutations of the Met receptor in hereditary papillary renal carcinomas have different signaling requirements for transformation than Tpr-Met. This suggests differential activation of membrane-localized pathways by oncogenic forms of the membrane-bound Met receptor but not by the cytoplasmic Tpr-Met oncoprotein. To establish which pathways might be differentially regulated, we have localized the constitutively activated Tpr-Met oncoprotein to the membrane using the c-src myristoylation signal. Membrane localization enhances cellular transformation, focus formation, and anchorage-independent growth and induces tumors with a distinct myxoid phenotype. This correlates with the induction of hyaluronic acid (HA) and the presence of a distinct form of its receptor, CD44. A pharmacological inhibitor of phosphoinositide 3' kinase (PI3'K), inhibits the production of HA, and conversely, an activated, plasma membrane-targeted form of PI3'K is sufficient to enhance HA production. Furthermore, the multisubstrate adapter protein Gab-1, which couples the Met receptor with PI3'K, enhances Met receptor-dependent HA synthesis in a PI3'K-dependent manner. These results provide a positive link to a role for HA and CD44 in Met receptor-mediated oncogenesis and implicate PI3'K in these events.

* Corresponding author. Mailing address: Molecular Oncology Group, McGill University Health Centre, Depts. of Medicine, Oncology, and Biochemistry, McGill University, H5.10, 687 Pine Ave. West, Montreal, Q.C., Canada, H3A-1A1. Phone: (514) 842-1231 ext. 5845. Fax: (514) 843-1478. E-mail: morag{at}lan1.molonc.mcgill.ca.

dagger Present address: Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024.

Molecular and Cellular Biology, May 2000, p. 3482-3496, Vol. 20, No. 10
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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