Mer receptor tyrosine kinase signaling: prevention of apoptosis and alteration of cytoskeletal architecture without stimulation or proliferation.
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 Mer cytoplasmic 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 G(1)/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.
Guttridge
Katherine L
KL
Lineberger Comprehensive Cancer Center, Department of Medicine and Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
Luft
J Christopher
JC
Dawson
Thomas L
TL
Kozlowska
Eva
E
Mahajan
Nupam P
NP
Varnum
Brian
B
Earp
H Shelton
HS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002448:Cell Adhesion; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D048429:Cell Size; D066246:ErbB Receptors; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D000076202:c-Mer Tyrosine Kinase
D007377:Interleukin-3; D019006:Neural Cell Adhesion Molecules; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D066246:ErbB Receptors; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases