A Rac-cGMP Signaling Pathway
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-activate...
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| Veröffentlicht in: | Cell 2007-01, Vol.128 (2), p.341-355 |
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| container_title | Cell |
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| creator | Guo, Dagang Tan, Ying-cai Wang, Dawei Madhusoodanan, K.S. Zheng, Yi Maack, Thomas Zhang, J. Jillian Huang, Xin-Yun |
| description | 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. |
| doi_str_mv | 10.1016/j.cell.2006.11.048 |
| format | Article |
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Jillian ; Huang, Xin-Yun</creator><creatorcontrib>Guo, Dagang ; Tan, Ying-cai ; Wang, Dawei ; Madhusoodanan, K.S. ; Zheng, Yi ; Maack, Thomas ; Zhang, J. Jillian ; Huang, Xin-Yun</creatorcontrib><description>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.</description><identifier>ISSN: 0092-8674</identifier><identifier>EISSN: 1097-4172</identifier><identifier>DOI: 10.1016/j.cell.2006.11.048</identifier><identifier>PMID: 17254971</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Cell Membrane - genetics ; Cell Membrane - metabolism ; Cell Movement - drug effects ; Cell Movement - physiology ; Cells, Cultured ; CHO Cells ; Cricetinae ; Cricetulus ; Cyclic GMP - metabolism ; Fibroblasts - drug effects ; Fibroblasts - metabolism ; Guanylate Cyclase - metabolism ; Humans ; Mice ; Mice, Knockout ; p21-Activated Kinases ; Platelet-Derived Growth Factor - metabolism ; Platelet-Derived Growth Factor - pharmacology ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; Pseudopodia - drug effects ; Pseudopodia - metabolism ; rac GTP-Binding Proteins - metabolism ; Signal Transduction - drug effects ; Signal Transduction - physiology ; Up-Regulation - drug effects ; Up-Regulation - physiology</subject><ispartof>Cell, 2007-01, Vol.128 (2), p.341-355</ispartof><rights>2007 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c429t-3ac7491502c0b96e7df9d3f8875282b9aaf617c9dabc4af8ea283dd1ab595b9a3</citedby><cites>FETCH-LOGICAL-c429t-3ac7491502c0b96e7df9d3f8875282b9aaf617c9dabc4af8ea283dd1ab595b9a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0092867407000025$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17254971$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Guo, Dagang</creatorcontrib><creatorcontrib>Tan, Ying-cai</creatorcontrib><creatorcontrib>Wang, Dawei</creatorcontrib><creatorcontrib>Madhusoodanan, K.S.</creatorcontrib><creatorcontrib>Zheng, Yi</creatorcontrib><creatorcontrib>Maack, Thomas</creatorcontrib><creatorcontrib>Zhang, J. Jillian</creatorcontrib><creatorcontrib>Huang, Xin-Yun</creatorcontrib><title>A Rac-cGMP Signaling Pathway</title><title>Cell</title><addtitle>Cell</addtitle><description>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.</description><subject>Animals</subject><subject>Cell Membrane - genetics</subject><subject>Cell Membrane - metabolism</subject><subject>Cell Movement - drug effects</subject><subject>Cell Movement - physiology</subject><subject>Cells, Cultured</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Cyclic GMP - metabolism</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - metabolism</subject><subject>Guanylate Cyclase - metabolism</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>p21-Activated Kinases</subject><subject>Platelet-Derived Growth Factor - metabolism</subject><subject>Platelet-Derived Growth Factor - pharmacology</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Pseudopodia - drug effects</subject><subject>Pseudopodia - metabolism</subject><subject>rac GTP-Binding Proteins - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - physiology</subject><subject>Up-Regulation - drug effects</subject><subject>Up-Regulation - physiology</subject><issn>0092-8674</issn><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1LAzEQhoMotlb_gIj05G3XTDbZJOBFilahYvHjHLJJtqZsd-tmq_Tfm6UFb3qawzzvO8yD0DngFDDk18vUuKpKCcZ5CpBiKg7QELDkCQVODtEQY0kSkXM6QCchLDHGgjF2jAZxzajkMEQXt-MXbRIzfZqPX_2i1pWvF-O57j6-9fYUHZW6Cu5sP0fo_f7ubfKQzJ6nj5PbWWIokV2SacOpBIaJwYXMHbeltFkpBGdEkEJqXebAjbS6MFSXwmkiMmtBF0yyuM5G6GrXu26bz40LnVr50P-ma9dsgsqFpAwY_AsSLCnEWxEkO9C0TQitK9W69SvdbhVg1ctTS9XnVC9PAagoL4Yu9-2bYuXsb2RvKwI3O8BFGV_etSoY72rjrG-d6ZRt_F_9P9T0fdQ</recordid><startdate>20070126</startdate><enddate>20070126</enddate><creator>Guo, Dagang</creator><creator>Tan, Ying-cai</creator><creator>Wang, Dawei</creator><creator>Madhusoodanan, K.S.</creator><creator>Zheng, Yi</creator><creator>Maack, Thomas</creator><creator>Zhang, J. Jillian</creator><creator>Huang, Xin-Yun</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20070126</creationdate><title>A Rac-cGMP Signaling Pathway</title><author>Guo, Dagang ; Tan, Ying-cai ; Wang, Dawei ; Madhusoodanan, K.S. ; Zheng, Yi ; Maack, Thomas ; Zhang, J. Jillian ; Huang, Xin-Yun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c429t-3ac7491502c0b96e7df9d3f8875282b9aaf617c9dabc4af8ea283dd1ab595b9a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>Cell Membrane - genetics</topic><topic>Cell Membrane - metabolism</topic><topic>Cell Movement - drug effects</topic><topic>Cell Movement - physiology</topic><topic>Cells, Cultured</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Cyclic GMP - metabolism</topic><topic>Fibroblasts - drug effects</topic><topic>Fibroblasts - metabolism</topic><topic>Guanylate Cyclase - metabolism</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>p21-Activated Kinases</topic><topic>Platelet-Derived Growth Factor - metabolism</topic><topic>Platelet-Derived Growth Factor - pharmacology</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Pseudopodia - drug effects</topic><topic>Pseudopodia - metabolism</topic><topic>rac GTP-Binding Proteins - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - physiology</topic><topic>Up-Regulation - drug effects</topic><topic>Up-Regulation - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Guo, Dagang</creatorcontrib><creatorcontrib>Tan, Ying-cai</creatorcontrib><creatorcontrib>Wang, Dawei</creatorcontrib><creatorcontrib>Madhusoodanan, K.S.</creatorcontrib><creatorcontrib>Zheng, Yi</creatorcontrib><creatorcontrib>Maack, Thomas</creatorcontrib><creatorcontrib>Zhang, J. 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Jillian</au><au>Huang, Xin-Yun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Rac-cGMP Signaling Pathway</atitle><jtitle>Cell</jtitle><addtitle>Cell</addtitle><date>2007-01-26</date><risdate>2007</risdate><volume>128</volume><issue>2</issue><spage>341</spage><epage>355</epage><pages>341-355</pages><issn>0092-8674</issn><eissn>1097-4172</eissn><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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>17254971</pmid><doi>10.1016/j.cell.2006.11.048</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; EZB Electronic Journals Library |
| subjects | Animals Cell Membrane - genetics Cell Membrane - metabolism Cell Movement - drug effects Cell Movement - physiology Cells, Cultured CHO Cells Cricetinae Cricetulus Cyclic GMP - metabolism Fibroblasts - drug effects Fibroblasts - metabolism Guanylate Cyclase - metabolism Humans Mice Mice, Knockout p21-Activated Kinases Platelet-Derived Growth Factor - metabolism Platelet-Derived Growth Factor - pharmacology Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Pseudopodia - drug effects Pseudopodia - metabolism rac GTP-Binding Proteins - metabolism Signal Transduction - drug effects Signal Transduction - physiology Up-Regulation - drug effects Up-Regulation - physiology |
| title | A Rac-cGMP Signaling Pathway |
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