title: Angiopoietin-like 4 interacts with matrix proteins to modulate wound healing.
abstract: 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.
authors: From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors: Yan Yih
authors: YY
authors: Goh
authors: From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors: Mintu
authors: M
authors: Pal
authors: From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors: Han Chung
authors: HC
authors: Chong
authors: From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors: Pengcheng
authors: P
authors: Zhu
authors: From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors: Ming Jie
authors: MJ
authors: Tan
authors: From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors: Lakshmi
authors: L
authors: Punugu
authors: From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors: Chek Kun
authors: CK
authors: Tan
authors: From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors: Royston-Luke
authors: RL
authors: Huang
authors: From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors: Siu Kwan
authors: SK
authors: Sze
authors: National Skin Centre, 1 Mandalay Road, Singapore 308205.
authors: Mark Boon Yang
authors: MBY
authors: Tang
authors: Department of Biological Sciences, National University of Singapore, 14 Science Drive, Singapore 117543.
authors: Jeak Ling
authors: JL
authors: Ding
authors: Wageningen University, 6700 EV Wageningen, The Netherlands.
authors: Sander
authors: S
authors: Kersten
authors: From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551. Electronic address: nstan@ntu.edu.sg.
authors: Nguan Soon
authors: NS
authors: Tan
mesh_terms: 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*
chemical_list: 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