STAT3 deficiency in keratinocytes leads to compromised cell migration through hyperphosphorylation of p130(cas).
We previously reported that STAT3 plays a crucial role in transducing a signal for migration of keratinocytes (Sano, S., Itami, S., Takeda, K., Tarutani, M., Yamaguchi, Y., Miura, H., Yoshikawa, K., Akira, S., and Takeda, J. (1999) EMBO J. 18, 4657-4668). To clarify the role of STAT3 in signaling the migration, we studied the intracellular signaling pathway through an integrin receptor in STAT3-deficient keratinocytes. STAT3-deficient keratinocytes demonstrated increased adhesiveness and fast spreading on a collagen matrix. Staining with anti-phosphotyrosine antibody revealed that STAT3-deficient keratinocytes had an increased number of tyrosyl-hyperphosphorylated focal adhesions. Analyses with immunoprecipitation revealed that p130(cas) was constitutively hyperphosphorylated on tyrosine residues, while other focal adhesion molecules such as focal adhesion kinase and paxillin were not. Transfection of STAT3-deficient keratinocytes with an adenoviral vector encoding the wild-type Stat3 gene reversed not only impaired migration but also the increased tyrosine phosphorylation of p130(cas). These results strongly suggest that STAT3 in keratinocytes plays a critical role in turnover of tyrosine phosphorylation of p130(cas), modulating cell adhesiveness to the substratum leading to growth factor-dependent cell migration.
Kira
Masahiro
M
Department of Dermatology, Course of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Sano
Shigetoshi
S
Takagi
Satoshi
S
Yoshikawa
Kunihiko
K
Takeda
Junji
J
Itami
Satoshi
S
D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D050719:Crk-Associated Substrate Protein; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D015603:Keratinocytes / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D011506:Proteins; D050717:Retinoblastoma-Like Protein p130; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014443:Tyrosine
C493842:Bcar1 protein, mouse; D050719:Crk-Associated Substrate Protein; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D011506:Proteins; D050717:Retinoblastoma-Like Protein p130; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014443:Tyrosine