Angiopoietin-like 4 interacts with integrins beta1 and beta5 to modulate keratinocyte migration.
Adipose tissue secretes adipocytokines for energy homeostasis, but recent evidence indicates that some adipocytokines also have a profound local impact on wound healing. Upon skin injury, keratinocytes use various signaling molecules to promote reepithelialization for efficient wound closure. In this study, we identify a novel function of adipocytokine angiopoietin-like 4 (ANGPTL4) in keratinocytes during wound healing through the control of both integrin-mediated signaling and internalization. Using two different in vivo models based on topical immuno-neutralization of ANGPTL4 as well as ablation of the ANGPTL4 gene, we show that ANGPTL4-deficient mice exhibit delayed wound reepithelialization with impaired keratinocyte migration. Human keratinocytes in which endogenous ANGPTL4 expression was suppressed by either siRNA or a neutralizing antibody show impaired migration associated with diminished integrin-mediated signaling. Importantly, we identify integrins β1 and β5, but not β3, as novel binding partners of ANGPTL4. ANGPTL4-bound integrin β1 activated the FAK-Src-PAK1 signaling pathway, which is important for cell migration. The findings presented herein reveal an unpredicted role of ANGPTL4 during wound healing and demonstrate how ANGPTL4 stimulates intracellular signaling mechanisms to coordinate cellular behavior. Our findings provide insight into a novel cell migration control mechanism and underscore the physiological importance of the modulation of integrin activity in cancer metastasis.
School of Biological Sciences, Nanyang Technological University, Singapore 637551.
Yan Yih
YY
Goh
Mintu
M
Pal
Han Chung
HC
Chong
Pengcheng
P
Zhu
Ming Jie
MJ
Tan
Lakshmi
L
Punugu
Chee Ren Ivan
CR
Lam
Yin Hoe
YH
Yau
Chek Kun
CK
Tan
Royston-Luke
RL
Huang
Suet Mien
SM
Tan
Mark Boon Yang
MB
Tang
Jeak Ling
JL
Ding
Sander
S
Kersten
Nguan Soon
NS
Tan
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D039641:Integrin beta Chains / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D021381:Protein Transport / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D012867:Skin / Q000293:injuries / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics / Q000502:physiology
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D039641:Integrin beta Chains; D019012:Integrin beta1; C084344:integrin beta5