Erythropoietin receptor Y479 couples to ERK1/2 activation via recruitment of phospholipase Cγ

Adrienne Halupa, Manprit Chohan, Natalie H. Stickle, Bryan K. Beattie, Barbara A. Miller, Dwayne L. Barber

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Red blood cell development is primarily controlled by erythropoietin (EPO). Several studies have revealed the importance of EPO-R Y343 and Y479 for erythroid cell growth, differentiation, and survival. In order to isolate critical signaling proteins that bind to EPO-R, we initiated a Cloning of Ligand Target (COLT) screen using a murine embryonic day 16 phage library and a biotinylated EPO-R Y343 phosphopeptide. One of the clones isolated encodes Phospholipase C (PLC)γ1. PLCγ1 is rapidly tyrosine phosphorylated upon EPO stimulation and associates with EPO-R in an SH2-domain-dependent manner. Although PLCγ1 bound EPO-R Y343, Y401, Y429, Y431, and Y479 in the COLT screen, PLCγ1 required Y479 for association with EPO-R in Ba/F3-EPO-R cells. Studies have identified EPO-R Y479 as important for ERK activation. Since PI3-kinase binds EPO-R Y479, one group has suggested that ERK activation downstream of PI3-kinase accounts for the importance of this residue in EPO signaling. However, we show that inhibition of PI3-kinase does not abolish ERK activation. Furthermore, we demonstrate interaction of PLCγ1 with Grb2 and SOS2. Hence, we have identified a novel adapter function for PLCγ1 in EPO signaling in which recruitment of PLCγ1 to EPO-R may lead to activation of the ERK pathway.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalExperimental Cell Research
Volume309
Issue number1
DOIs
StatePublished - Sep 10 2005

All Science Journal Classification (ASJC) codes

  • Cell Biology

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