Angiopoietin-like 4 interacts with matrix proteins to modulate wound healing.
A dynamic cell-matrix interaction is crucial for a rapid cellular response to changes in the environment. Appropriate cell behavior in response to the changing wound environment is required for efficient wound closure. However, the way in which wound keratinocytes modify the wound environment to coordinate with such cellular responses remains less studied. We demonstrated that angiopoietin-like 4 (ANGPTL4) produced by wound keratinocytes coordinates cell-matrix communication. ANGPTL4 interacts with vitronectin and fibronectin in the wound bed, delaying their proteolytic degradation by metalloproteinases. This interaction does not interfere with integrin-matrix protein recognition and directly affects cell-matrix communication by altering the availability of intact matrix proteins. These interactions stimulate integrin- focal adhesion kinase, 14-3-3, and PKC-mediated signaling pathways essential for effective wound healing. The deficiency of ANGPTL4 in mice delays wound re-epithelialization. Further analysis revealed that cell migration was impaired in the ANGPTL4-deficient keratinocytes. Altogether, the findings provide molecular insight into a novel control of wound healing via ANGPTL4-dependent regulation of cell-matrix communication. Given the known role of ANGPTL4 in glucose and lipid homeostasis, it is a prime therapeutic candidate for the treatment of diabetic wounds. It also underscores the importance of cell-matrix communication during angiogenesis and cancer metastasis.
Goh
Yan Yih
YY
From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
Pal
Mintu
M
From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
Chong
Han Chung
HC
From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
Zhu
Pengcheng
P
From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
Tan
Ming Jie
MJ
From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
Punugu
Lakshmi
L
From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
Tan
Chek Kun
CK
From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
Huang
Royston-Luke
RL
From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
Sze
Siu Kwan
SK
From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
Tang
Mark Boon Yang
MBY
National Skin Centre, 1 Mandalay Road, Singapore 308205.
Ding
Jeak Ling
JL
Department of Biological Sciences, National University of Singapore, 14 Science Drive, Singapore 117543.
Kersten
Sander
S
Wageningen University, 6700 EV Wageningen, The Netherlands.
Tan
Nguan Soon
NS
From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551. Electronic address: nstan@ntu.edu.sg.
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D048909:Diabetes Complications / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014945:Wound Healing; D014947:Wounds and Injuries / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*
D048948:14-3-3 Proteins; C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D016326:Extracellular Matrix Proteins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D011493:Protein Kinase C