Additive effects of PDGF receptor beta signaling pathways in vascular smooth muscle cell development.
The platelet-derived growth factor beta receptor (PDGFRbeta) is known to activate many molecules involved in signal transduction and has been a paradigm for receptor tyrosine kinase signaling for many years. We have sought to determine the role of individual signaling components downstream of this receptor in vivo by analyzing an allelic series of tyrosine-phenylalanine mutations that prevent binding of specific signal transduction components. Here we show that the incidence of vascular smooth muscle cells/pericytes (v/p), a PDGFRbeta-dependent cell type, can be correlated to the amount of receptor expressed and the number of activated signal transduction pathways. A decrease in either receptor expression levels or disruption of multiple downstream signaling pathways lead to a significant reduction in v/p. Conversely, loss of RasGAP binding leads to an increase in this same cell population, implicating a potential role for this effector in attenuating the PDGFRbeta signal. The combined in vivo and biochemical data suggest that the summation of pathways associated with the PDGFRbeta signal transduction determines the expansion of developing v/p cells.
Tallquist
Michelle D
MD
Program in Developmental Biology and Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. michelle.tallquist@utsouthwestern.edu
French
Wendy J
WJ
Soriano
Philippe
P
D000483:Alleles; D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D003593:Cytoplasm / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D020286:Pericytes / Q000378:metabolism; D010649:Phenylalanine / Q000737:chemistry; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000502:physiology*; D012160:Retina / Q000196:embryology; D015398:Signal Transduction; D013997:Time Factors; D019076:Transgenes; D014443:Tyrosine / Q000737:chemistry
D014443:Tyrosine; D010649:Phenylalanine; D020794:Receptor Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta