Directional sensing requires G beta gamma-mediated PAK1 and PIX alpha-dependent activation of Cdc42
Efficient chemotaxis requires directional sensing and cell polarization. We describe a signaling mechanism involving G beta gamma, PAK-associated guanine nucleotide exchange factor (PIX alpha), Cdc42, and p21-activated kinase (PAK) 1. This pathway is utilized by chemoattractants to regulate directio...
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| Veröffentlicht in: | Cell 2003-07, Vol.114 (2), p.215-227 |
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| container_title | Cell |
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| creator | Li, Zhong Hannigan, Michael Mo, Zhicheng Liu, Bo Lu, Wei Wu, Yue Smrcka, Alan V Wu, Guanqing Li, Lin Liu, Mingyao Huang, Chi-Kuang Wu, Dianqing |
| description | Efficient chemotaxis requires directional sensing and cell polarization. We describe a signaling mechanism involving G beta gamma, PAK-associated guanine nucleotide exchange factor (PIX alpha), Cdc42, and p21-activated kinase (PAK) 1. This pathway is utilized by chemoattractants to regulate directional sensing and directional migration of myeloid cells. Our results suggest that G beta gamma binds PAK1 and, via PAK-associated PIX alpha, activates Cdc42, which in turn activates PAK1. Thus, in this pathway, PAK1 is not only an effector for Cdc42, but it also functions as a scaffold protein required for Cdc42 activation. This G beta gamma-PAK1/PIX alpha/Cdc42 pathway is essential for the localization of F-actin formation to the leading edge, the exclusion of PTEN from the leading edge, directional sensing, and the persistent directional migration of chemotactic leukocytes. Although ligand-induced production of PIP(3) is not required for activation of this pathway, PIP(3) appears to localize the activation of Cdc42 by the pathway. |
| doi_str_mv | 10.1016/S0092-8674(03)00559-2 |
| format | Article |
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We describe a signaling mechanism involving G beta gamma, PAK-associated guanine nucleotide exchange factor (PIX alpha), Cdc42, and p21-activated kinase (PAK) 1. This pathway is utilized by chemoattractants to regulate directional sensing and directional migration of myeloid cells. Our results suggest that G beta gamma binds PAK1 and, via PAK-associated PIX alpha, activates Cdc42, which in turn activates PAK1. Thus, in this pathway, PAK1 is not only an effector for Cdc42, but it also functions as a scaffold protein required for Cdc42 activation. This G beta gamma-PAK1/PIX alpha/Cdc42 pathway is essential for the localization of F-actin formation to the leading edge, the exclusion of PTEN from the leading edge, directional sensing, and the persistent directional migration of chemotactic leukocytes. Although ligand-induced production of PIP(3) is not required for activation of this pathway, PIP(3) appears to localize the activation of Cdc42 by the pathway.</description><identifier>ISSN: 0092-8674</identifier><identifier>DOI: 10.1016/S0092-8674(03)00559-2</identifier><identifier>PMID: 12887923</identifier><language>eng</language><publisher>United States</publisher><subject>Actins - metabolism ; Animals ; cdc42 GTP-Binding Protein - metabolism ; Cell Polarity - drug effects ; Cercopithecus aethiops ; Chemotaxis ; Complement C5a - pharmacology ; COS Cells ; Enzyme Activation ; Gene Expression Regulation, Enzymologic ; Guanine Nucleotide Exchange Factors - genetics ; Guanine Nucleotide Exchange Factors - metabolism ; Heterotrimeric GTP-Binding Proteins - metabolism ; Humans ; Mice ; Mice, Knockout ; Models, Biological ; Neutrophils - drug effects ; Neutrophils - metabolism ; Phosphatidylinositol 3-Kinases - metabolism ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; Signal Transduction ; Transfection</subject><ispartof>Cell, 2003-07, Vol.114 (2), p.215-227</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c222t-843b4f19aa5edae205c3489cadf8db56e418cfea89a4788ce3ed99c8d965f0863</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12887923$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Zhong</creatorcontrib><creatorcontrib>Hannigan, Michael</creatorcontrib><creatorcontrib>Mo, Zhicheng</creatorcontrib><creatorcontrib>Liu, Bo</creatorcontrib><creatorcontrib>Lu, Wei</creatorcontrib><creatorcontrib>Wu, Yue</creatorcontrib><creatorcontrib>Smrcka, Alan V</creatorcontrib><creatorcontrib>Wu, Guanqing</creatorcontrib><creatorcontrib>Li, Lin</creatorcontrib><creatorcontrib>Liu, Mingyao</creatorcontrib><creatorcontrib>Huang, Chi-Kuang</creatorcontrib><creatorcontrib>Wu, Dianqing</creatorcontrib><title>Directional sensing requires G beta gamma-mediated PAK1 and PIX alpha-dependent activation of Cdc42</title><title>Cell</title><addtitle>Cell</addtitle><description>Efficient chemotaxis requires directional sensing and cell polarization. We describe a signaling mechanism involving G beta gamma, PAK-associated guanine nucleotide exchange factor (PIX alpha), Cdc42, and p21-activated kinase (PAK) 1. This pathway is utilized by chemoattractants to regulate directional sensing and directional migration of myeloid cells. Our results suggest that G beta gamma binds PAK1 and, via PAK-associated PIX alpha, activates Cdc42, which in turn activates PAK1. Thus, in this pathway, PAK1 is not only an effector for Cdc42, but it also functions as a scaffold protein required for Cdc42 activation. This G beta gamma-PAK1/PIX alpha/Cdc42 pathway is essential for the localization of F-actin formation to the leading edge, the exclusion of PTEN from the leading edge, directional sensing, and the persistent directional migration of chemotactic leukocytes. Although ligand-induced production of PIP(3) is not required for activation of this pathway, PIP(3) appears to localize the activation of Cdc42 by the pathway.</description><subject>Actins - metabolism</subject><subject>Animals</subject><subject>cdc42 GTP-Binding Protein - metabolism</subject><subject>Cell Polarity - drug effects</subject><subject>Cercopithecus aethiops</subject><subject>Chemotaxis</subject><subject>Complement C5a - pharmacology</subject><subject>COS Cells</subject><subject>Enzyme Activation</subject><subject>Gene Expression Regulation, Enzymologic</subject><subject>Guanine Nucleotide Exchange Factors - genetics</subject><subject>Guanine Nucleotide Exchange Factors - metabolism</subject><subject>Heterotrimeric GTP-Binding Proteins - metabolism</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Models, Biological</subject><subject>Neutrophils - drug effects</subject><subject>Neutrophils - metabolism</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Signal Transduction</subject><subject>Transfection</subject><issn>0092-8674</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkEtLw0AUhWeh2Fr9CcqsRBfReSYzy1K1FgsKKrgLNzM3NZJXM4ngvzdidevqXA4fH9xDyAlnl5zx-OqJMSsiEyfqnMkLxrS2kdgj0796Qg5DeGeMGa31AZlwYUxihZwSd1106PqiqaGkAetQ1Bva4XYY60CXNMMe6AaqCqIKfQE9evo4v-cU6vFYvVIo2zeIPLZYe6x7CqPsA76FtMnpwjsljsh-DmXA413OyMvtzfPiLlo_LFeL-TpyQog-MkpmKucWQKMHFEw7qYx14HPjMx2j4sblCMaCSoxxKNFb64y3sc6ZieWMnP14267ZDhj6tCqCw7KEGpshpInUXOg4-RfkxjAtYzWCpztwyMb307YrKug-09_95BeWm3D0</recordid><startdate>20030725</startdate><enddate>20030725</enddate><creator>Li, Zhong</creator><creator>Hannigan, Michael</creator><creator>Mo, Zhicheng</creator><creator>Liu, Bo</creator><creator>Lu, Wei</creator><creator>Wu, Yue</creator><creator>Smrcka, Alan V</creator><creator>Wu, Guanqing</creator><creator>Li, Lin</creator><creator>Liu, Mingyao</creator><creator>Huang, Chi-Kuang</creator><creator>Wu, Dianqing</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7T5</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20030725</creationdate><title>Directional sensing requires G beta gamma-mediated PAK1 and PIX alpha-dependent activation of Cdc42</title><author>Li, Zhong ; Hannigan, Michael ; Mo, Zhicheng ; Liu, Bo ; Lu, Wei ; Wu, Yue ; Smrcka, Alan V ; Wu, Guanqing ; Li, Lin ; Liu, Mingyao ; Huang, Chi-Kuang ; Wu, Dianqing</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c222t-843b4f19aa5edae205c3489cadf8db56e418cfea89a4788ce3ed99c8d965f0863</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Actins - metabolism</topic><topic>Animals</topic><topic>cdc42 GTP-Binding Protein - metabolism</topic><topic>Cell Polarity - drug effects</topic><topic>Cercopithecus aethiops</topic><topic>Chemotaxis</topic><topic>Complement C5a - pharmacology</topic><topic>COS Cells</topic><topic>Enzyme Activation</topic><topic>Gene Expression Regulation, Enzymologic</topic><topic>Guanine Nucleotide Exchange Factors - genetics</topic><topic>Guanine Nucleotide Exchange Factors - metabolism</topic><topic>Heterotrimeric GTP-Binding Proteins - metabolism</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Models, Biological</topic><topic>Neutrophils - drug effects</topic><topic>Neutrophils - metabolism</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Signal Transduction</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Zhong</creatorcontrib><creatorcontrib>Hannigan, Michael</creatorcontrib><creatorcontrib>Mo, Zhicheng</creatorcontrib><creatorcontrib>Liu, Bo</creatorcontrib><creatorcontrib>Lu, Wei</creatorcontrib><creatorcontrib>Wu, Yue</creatorcontrib><creatorcontrib>Smrcka, Alan V</creatorcontrib><creatorcontrib>Wu, Guanqing</creatorcontrib><creatorcontrib>Li, Lin</creatorcontrib><creatorcontrib>Liu, Mingyao</creatorcontrib><creatorcontrib>Huang, Chi-Kuang</creatorcontrib><creatorcontrib>Wu, Dianqing</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Zhong</au><au>Hannigan, Michael</au><au>Mo, Zhicheng</au><au>Liu, Bo</au><au>Lu, Wei</au><au>Wu, Yue</au><au>Smrcka, Alan V</au><au>Wu, Guanqing</au><au>Li, Lin</au><au>Liu, Mingyao</au><au>Huang, Chi-Kuang</au><au>Wu, Dianqing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Directional sensing requires G beta gamma-mediated PAK1 and PIX alpha-dependent activation of Cdc42</atitle><jtitle>Cell</jtitle><addtitle>Cell</addtitle><date>2003-07-25</date><risdate>2003</risdate><volume>114</volume><issue>2</issue><spage>215</spage><epage>227</epage><pages>215-227</pages><issn>0092-8674</issn><abstract>Efficient chemotaxis requires directional sensing and cell polarization. We describe a signaling mechanism involving G beta gamma, PAK-associated guanine nucleotide exchange factor (PIX alpha), Cdc42, and p21-activated kinase (PAK) 1. This pathway is utilized by chemoattractants to regulate directional sensing and directional migration of myeloid cells. Our results suggest that G beta gamma binds PAK1 and, via PAK-associated PIX alpha, activates Cdc42, which in turn activates PAK1. Thus, in this pathway, PAK1 is not only an effector for Cdc42, but it also functions as a scaffold protein required for Cdc42 activation. This G beta gamma-PAK1/PIX alpha/Cdc42 pathway is essential for the localization of F-actin formation to the leading edge, the exclusion of PTEN from the leading edge, directional sensing, and the persistent directional migration of chemotactic leukocytes. Although ligand-induced production of PIP(3) is not required for activation of this pathway, PIP(3) appears to localize the activation of Cdc42 by the pathway.</abstract><cop>United States</cop><pmid>12887923</pmid><doi>10.1016/S0092-8674(03)00559-2</doi><tpages>13</tpages></addata></record> |
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| subjects | Actins - metabolism Animals cdc42 GTP-Binding Protein - metabolism Cell Polarity - drug effects Cercopithecus aethiops Chemotaxis Complement C5a - pharmacology COS Cells Enzyme Activation Gene Expression Regulation, Enzymologic Guanine Nucleotide Exchange Factors - genetics Guanine Nucleotide Exchange Factors - metabolism Heterotrimeric GTP-Binding Proteins - metabolism Humans Mice Mice, Knockout Models, Biological Neutrophils - drug effects Neutrophils - metabolism Phosphatidylinositol 3-Kinases - metabolism Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Signal Transduction Transfection |
| title | Directional sensing requires G beta gamma-mediated PAK1 and PIX alpha-dependent activation of Cdc42 |
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