Activation of small GTPase Rho is required for autocrine motility factor signaling.
The hallmark of tumor metastasis is the dissemination of cells from the primary growth site to distant organs. Autocrine motility factor (AMF), a tumor-associated C-X-X-C cytokine, the ligand for a unique 78 kDa seven transmembrane receptor, is a potent simulator of cell motility, a process that is a prerequisite for tumor progression and metastasis. Because little is known about AMF-dependent signaling, we sought to study whether AMF signaling involves family members of the Rho-like GTPases. AMF stimulation of human melanoma cells resulted in stress-fiber formation, concomitant with up-regulation and activation of both RhoA and Rac1 expression with no apparent changes in the expression level or activation state of Cdc42. Treatment of the cells with C3 exoenzyme before AMF stimulation inhibited both the formation of stress-fiber-like structures and the activation of RhoA. In addition, both c-Jun NH(2)-terminal kinase 1 and c-Jun NH(2)-terminal kinase 2 were simultaneously activated by AMF, supporting the notion that they are involved in the signaling pathway of RhoA. We thus conclude that AMF signaling shares a similar pathway to previously established paracrine factors signaling involving cytoskeletal rearrangement and morphological alterations mediated by the small RhoA-like GTPases.
Tsutsumi
Soichi
S
Metastasis Research Program, Karmanos Cancer Institute and the Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Gupta
Suresh K
SK
Hogan
Victor
V
Collard
John G
JG
Raz
Avraham
A
D036002:ADP Ribose Transferases / Q000494:pharmacology; D001905:Botulinum Toxins; D002465:Cell Movement / Q000502:physiology; D003599:Cytoskeleton / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D005354:Fibrosarcoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005956:Glucose-6-Phosphate Isomerase / Q000502:physiology*; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D060285:Receptors, Autocrine Motility Factor; D018121:Receptors, Cytokine / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D022502:Stress Fibers / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D044767:Ubiquitin-Protein Ligases; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D018121:Receptors, Cytokine; C555000:AMFR protein, human; D060285:Receptors, Autocrine Motility Factor; D044767:Ubiquitin-Protein Ligases; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D001905:Botulinum Toxins; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D005956:Glucose-6-Phosphate Isomerase