alpha3beta1 integrin promotes cell survival via multiple interactions between 14-3-3 isoforms and proapoptotic proteins.
Laminin-5 and alpha3beta1 integrin promote keratinocyte survival; however, the downstream signaling pathways for laminin-5/alpha3beta1 integrin-mediated cell survival had not been fully established. We report the unexpected finding of multiple interactions between 14-3-3 isoforms and proapoptotic proteins in the survival signaling pathway. Ln5-P4 motif within human laminin-5 alpha3 chain promotes cell survival and anti-apoptosis by inactivating Bad and YAP. This effect is achieved through the formation of 14-3-3zeta/p-Bad and 14-3-3sigma/p-YAP complexes, which is initiated by alpha3beta1 integrin and FAK/PI3K/Akt signaling. These complexes result in cytoplasmic sequestration of Bad and YAP and their subsequent inactivation. An increase in Akt1 activity in cells induces 14-3-3zeta and sigma, p-Bad, and p-YAP, promoting cell survival, whereas decreasing Akt activity suppresses the same proteins and inhibits cell survival. Suppression of 14-3-3zeta with RNA-interference inhibits cell viability and promotes apoptosis. These results reveal a new mechanism of cell survival whereby the formation of 14-3-3zeta/p-Bad and 14-3-3sigma/p-YAP complexes is initiated by laminin-5 stimulation via the alpha3beta1 integrin and FAK/PI3K/Akt signaling pathways, thereby resulting in cell survival and anti-apoptosis.
Oh
Ju-Eun
JE
Department of Oral Biochemistry and Program of Craniomaxillofacial Reconstruction Science, Dental Research Institute, BK21 CLS, and IBEC, Seoul National University School of Dentistry, Seoul 110-749, Korea.
Jang
Da Hyun
DH
Kim
Hyunsoo
H
Kang
Hyun Ki
HK
Chung
Chong-Pyoung
CP
Park
Won Ho
WH
Min
Byung-Moo
BM
D048948:14-3-3 Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000494:pharmacology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002675:Child, Preschool; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1 / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D007223:Infant; D039201:Integrin alpha3beta1 / Q000187:drug effects / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009687:Nuclear Proteins / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D014945:Wound Healing; D051025:bcl-Associated Death Protein / Q000187:drug effects / Q000378:metabolism; D000097794:Kalinin
D048948:14-3-3 Proteins; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D002867:Chromones; D004791:Enzyme Inhibitors; D051417:Focal Adhesion Kinase 1; D039201:Integrin alpha3beta1; D009025:Morpholines; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D014157:Transcription Factors; D051025:bcl-Associated Death Protein; D000097794:Kalinin; C494819:BAD protein, human; C456659:YY1AP1 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C496050:PTK2 protein, human