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The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
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The hyaluronan receptor RHAMM regulates extracellular-regulated kinase

S Zhang1, M C Chang, D Zylka

  • 1Hospital for Sick Children, Division of Cardiovascular Research, Toronto, Ontario, Canada M5G1X8.

The Journal of Biological Chemistry
|June 6, 1998
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Summary

Receptor for hyaluronan-mediated motility (RHAMM) isoforms regulate Ras-ERK signaling. RHAMM variant 4 (RHAMMv4) acts downstream of Ras, influencing mitogen-activated protein kinase kinase and ERK interactions, and activating ERK signaling.

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Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Signal Transduction

Background:

  • Two isoforms of receptor for hyaluronan-mediated motility (RHAMM) encode an alternatively spliced exon 4.
  • RHAMM variant 4 (RHAMMv4) is transforming upon overexpression and regulates Ras signaling.
  • RHAMM isoforms are found on the cell surface and in the cytoplasm, while RHAMMv4 is exclusively cytoplasmic.

Purpose of the Study:

  • To investigate the roles of RHAMM isoforms, particularly RHAMMv4, in regulating extracellular-regulated kinase (ERK) activity.
  • To elucidate the mechanism by which RHAMMv4 influences the Ras-ERK signaling pathway.

Main Methods:

  • Flow cytometry and confocal analysis to determine RHAMM localization.
  • Epitope-tagging experiments to differentiate RHAMM isoform localization.
  • Affinity-purified anti-RHAMM exon 4 antibodies to assess effects on ERK activation.
  • Dominant-negative RHAMMv4 to study its interaction with signaling components.
  • Coimmunoprecipitation assays to analyze protein interactions within the Ras-ERK pathway.

Main Results:

  • RHAMM isoforms encoding exon 4 are present on the cell surface and in the cytoplasm; RHAMMv4 is localized to the cytoplasm.
  • Anti-RHAMM exon 4 antibodies inhibit platelet-derived growth factor-induced ERK activation and alter protein tyrosine phosphorylation.
  • Dominant-negative RHAMMv4 inhibits Ras-mediated ERK activation and interacts with mitogen-activated protein kinase kinase (MEK) and ERK.
  • Overexpression of RHAMMv4 leads to constitutive ERK activation.

Conclusions:

  • RHAMM isoforms, including cytoplasmic RHAMMv4, play a significant role in regulating the Ras-ERK signaling pathway.
  • RHAMMv4 functions downstream of Ras, potentially modulating MEK-ERK interactions.
  • These findings reveal a novel mechanism for Ras-ERK pathway regulation involving RHAMM.