Mer receptor tyrosine kinase signaling: Prevention of apoptosis and alteration of cytoskeletal architecture without stimulation or proliferation

Katherine L. Guttridge, J. Christopher Luft, Thomas L. Dawson, Eva Kozlowska, Nupam P. Mahajan, Brian Varnum, H. Shelton Earp

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

Mer is a member of the Axl/Mer/Tyro3 receptor tyrosine kinase family, a family whose physiological function is not well defined. We constructed a Mer chimera using the epidermal growth factor receptor (EGFR) extracellular and transmembrane domains and the Mercytoplasmic domain. Stable transfection of the Mer chimera into interleukin 3 (IL-3)-dependent murine 32D cells resulted in ligand-activable surface receptor that tyrosine autophosphorylated, stimulated intracellular signaling, and dramatically reduced apoptosis initiated by IL-3 withdrawal. However, unlike multiple other ectopically expressed receptor tyrosine kinases including full-length EGFR or an EGFR/Axl chimera, the Mer chimera did not stimulate proliferation. Moreover, and in contrast to EGFR, Mer chimera activation induced adherence and cell flattening in the normally suspension-growing 32D cells. The Mer chimera signal also blocked IL-3-dependent proliferation leading to G1/S arrest, dephosphorylation of retinoblastoma protein, and elongation of cellular processes. Unlike other agonists that lead to a slow (4-8 days) ligand-dependent differentiation of 32D cells, the combined Mer and IL-3 signal resulted in differentiated morphology and growth cessation in the first 24 h. Thus the Mer chimera blocks apoptosis without stimulating growth and produces cytoskeletal alterations; this outcome is clearly separable from the proliferative signal produced by most receptor tyrosine kinases.

Original languageEnglish
Pages (from-to)24057-24066
Number of pages10
JournalJournal of Biological Chemistry
Volume277
Issue number27
DOIs
StatePublished - Jul 5 2002

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