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Molecular and Cellular Biology, May 2000, p. 3482-3496, Vol. 20, No. 10
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.
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

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