Chemokines integrate JAK/STAT and G-protein pathways during chemotaxis and calcium flux responses.
The JAK/STAT (Janus kinase / signaling transducer and activator of transcription) signaling pathway is implicated in converting stationary epithelial cells to migratory cells. In mammals, migratory responses are activated by chemoattractant proteins, including chemokines. We found that by binding to seven-transmembrane G-protein-coupled receptors, chemokines activate the JAK/STAT pathway to trigger chemotactic responses. We show that chemokine-mediated JAK/STAT activation is critical for G-protein induction and for phospholipase C-beta dependent Ca(2+) flux; in addition, pharmacological inhibition of JAK or mutation of the JAK kinase domain causes defects in both responses. Furthermore, G alpha(i) association with the receptor is dependent on JAK activation, and the chemokine-mediated Ca(2+) flux that requires phospholipase C-beta activity takes place downstream of JAK kinases. The chemokines thus employ a mechanism that links heterologous signaling pathways--G proteins and tyrosine kinases--in a network that may be essential for mediating their pleiotropic responses.
Department of Immunology and Oncology, Centro Nacional de Biotecnología, Madrid, Spain.
Silvia F
SF
Soriano
Antonio
A
Serrano
Patricia
P
Hernanz-Falcón
Ana
A
Martín de Ana
María
M
Monterrubio
Carlos
C
Martínez
J Miguel
JM
Rodríguez-Frade
Mario
M
Mellado
D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D054377:Chemokine CXCL12; D018925:Chemokines / Q000502:physiology*; D019743:Chemokines, CXC / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000502:physiology; D053614:Janus Kinase 2; D054799:Phospholipase C beta; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D019718:Receptors, CXCR4 / Q000502:physiology; D011956:Receptors, Cell Surface / Q000502:physiology; D010738:Type C Phospholipases / Q000502:physiology
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; D007527:Isoenzymes; D011518:Proto-Oncogene Proteins; D019718:Receptors, CXCR4; D011956:Receptors, Cell Surface; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D010738:Type C Phospholipases; D054799:Phospholipase C beta; D019204:GTP-Binding Proteins; D002118:Calcium