Midkine promotes tetraspanin-integrin interaction and induces FAK-Stat1alpha pathway contributing to migration/invasiveness of human head and neck squamous cell carcinoma cells.
The heparin-binding growth factor, MK, promoting tumorigenesis and survival was found to associate with alpha6beta1 integrins. We showed for the first time that MK interacted with TSPAN1 and facilitated the association between TSPAN1 and integrin alpha6beta1 proteins in head and neck squamous cell carcinoma (HNSCC) cells. We found that MK mediated an integrin-dependent tyrosine phosphorylation of FAK and activation of paxillin and Stat1alpha pathways. As result, downstream target genes implicated in cell migration and invasiveness (e.g. MMP-2 and MMP-26) were overexpressed. We observed that RNAi silencing of the critical signaling intermediates led to decrease of MK-induced migration/invasiveness of HNSCC cells. The major finding of this study is a novel MK-triggered signaling mechanism implicated in migration and invasiveness of HNSCC cells.
Department of Dermatology, The Johns Hopkins University School of Medicine, David H. Koch Cancer Research Building, Rm 2M05, 1550 Orleans Street, Baltimore, MD 21231, USA.
Yiping
Y
Huang
Department of Dermatology, The Johns Hopkins University School of Medicine, David H. Koch Cancer Research Building, Rm 2M05, 1550 Orleans Street, Baltimore, MD 21231, USA.
Myoung
M
Sook-Kim
Department of Dermatology, The Johns Hopkins University School of Medicine, David H. Koch Cancer Research Building, Rm 2M05, 1550 Orleans Street, Baltimore, MD 21231, USA. Electronic address: eratovi1@jhmi.edu.
Edward
E
Ratovitski
D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D052138:Genes, Neoplasm; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D039121:Integrin alpha6beta1 / Q000378:metabolism*; D050832:Interferon-Stimulated Gene Factor 3 / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D000078792:Midkine; D009361:Neoplasm Invasiveness; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D059470:Tetraspanins; D020798:Two-Hybrid System Techniques
D039121:Integrin alpha6beta1; D050832:Interferon-Stimulated Gene Factor 3; C066254:MDK protein, human; D008565:Membrane Proteins; D009414:Nerve Growth Factors; C508125:TSPAN1 protein, human; D059470:Tetraspanins; C079868:gamma interferon activation factor; D000078792:Midkine; D051417:Focal Adhesion Kinase 1