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PMID: 17254971 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

A Rac-cGMP signaling pathway.

Cell ·Vol. 128 ·No. 2 ·2007-01-26 ·Pages 341-55

Guo D, Tan YC, Wang D, Madhusoodanan KS, Zheng Y, Maack T, Zhang JJ, Huang XY

Abstract

The small GTPase Rac and the second messenger cGMP (guanosine 3',5'-cyclic monophosphate) are critical regulators of diverse cell functions. When activated by extracellular signals via membrane signaling receptors, Rac executes its functions through engaging downstream effectors such as p21-activated kinase (PAK), a serine/threonine protein kinase. However, the molecular mechanism by which membrane signaling receptors regulate cGMP levels is not known. Here we have uncovered a signaling pathway linking Rac to the increase of cellular cGMP. We show that Rac uses PAK to directly activate transmembrane guanylyl cyclases (GCs), leading to increased cellular cGMP levels. This Rac/PAK/GC/cGMP pathway is involved in platelet-derived growth factor-induced fibroblast cell migration and lamellipodium formation. Our findings connect two important regulators of cellular physiological functions and provide a general mechanism for diverse receptors to modulate physiological responses through elevating cellular cGMP levels.

MeSH Terms
Animals CHO Cells Cell Membrane/genetics,metabolism Cell Movement/drug effects,physiology Cells, Cultured Cricetinae Cricetulus Cyclic GMP/metabolism Fibroblasts/drug effects,metabolism Guanylate Cyclase/metabolism Humans Mice Mice, Knockout Platelet-Derived Growth Factor/metabolism,pharmacology Protein Serine-Threonine Kinases/genetics,metabolism Pseudopodia/drug effects,metabolism Signal Transduction/drug effects,physiology Up-Regulation/drug effects,physiology p21-Activated Kinases rac GTP-Binding Proteins/metabolism
Chemicals
Platelet-Derived Growth Factor PAK1 protein, human Pak1 protein, mouse Protein Serine-Threonine Kinases p21-Activated Kinases rac GTP-Binding Proteins Guanylate Cyclase Cyclic GMP
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Guo Dagang
Department of Physiology, Cornell University Weill Medical College, New York, NY 10021, and Division of Experimental Hematology, Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
Tan Ying-cai
Wang Dawei
Madhusoodanan K S
Zheng Yi
Maack Thomas
Zhang J Jillian
Huang Xin-Yun
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
0092-8674
DOI
10.1016/j.cell.2006.11.048
Published
2007-01-26
Pages
341-55
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC1965458
Subset
IM
Grants
NIA NIH HHS · AG14563 · United States
NIGMS NIH HHS · R01 GM056904 · United States
NIA NIH HHS · R01 AG023202 · United States
NIGMS NIH HHS · R01 GM084191 · United States
NIA NIH HHS · AG23202 · United States
NIGMS NIH HHS · GM56904 · United States
NIA NIH HHS · R01 AG014563 · United States
Corrections
CommentIn
PMID: 17254961
External Links
PubMed source DOI: 10.1016/j.cell.2006.11.048 PMC Full Text View journal details
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