TY - JOUR
T1 - The anti-motility signaling mechanism of TGFβ3 that controls cell traffic during skin wound healing
AU - Han, Arum
AU - Bandyopadhyay, Balaji
AU - Jayaprakash, Priyamvada
AU - Lua, Ingrid
AU - Sahu, Divya
AU - Chen, Mei
AU - Woodley, David T.
AU - Li, Wei
N1 - Funding Information:
This study was supported by NIH grants GM066193 and GM067100 (to W.L.), AR46538 (to D.T.W.) and AR33625 (M.C. and D.T.W.).
Publisher Copyright:
© 2012 Published by The Company of Biologists Ltd.
PY - 2012/12/15
Y1 - 2012/12/15
N2 - When skin is wounded, migration of epidermal keratinocytes at the wound edge initiates within hours, whereas migration of dermal fibroblasts toward the wounded area remains undetectable until several days later. This "cell type traffic" regulation ensures proper healing of the wound, as disruptions of the regulation could either cause delay of wound healing or result in hypertrophic scars. TGFβ3 is the critical traffic controller that selectively halts migration of the dermal, but not epidermal, cells to ensure completion of wound re-epithelialization prior to wound remodeling. However, the mechanism of TGFβ3's anti-motility signaling has never been investigated. We report here that activated TbRII transmits the anti-motility signal of TGFβ3 in full to TbRI, since expression of the constitutively activated TbRITD mutant was sufficient to replace TGFβ3 to block PDGFbb-induced dermal fibroblast migration. Second, the three components of R-Smad complex are all required. Individual downregulation of Smad2, Smad3 or Smad4 prevented TGFβ3 from inhibiting dermal fibroblast migration. Third, Protein Kinase Array allowed us to identify the protein kinase A (PKA) as a specific downstream effector of R-Smads in dermal fibroblasts. Activation of PKA alone blocked PDGF-bb-induced dermal fibroblast migration, just like TGFβ3. Downregulation of PKA's catalytic subunit nullified the anti-motility signaling of TGFβ3. This is the first report on anti-motility signaling mechanism by TGFβ family cytokines. Significance of this finding is not only limited to wound healing but also to other human disorders, such as heart attack and cancer, where the diseased cells have often managed to avoid the anti-motility effect of TGFβ.
AB - When skin is wounded, migration of epidermal keratinocytes at the wound edge initiates within hours, whereas migration of dermal fibroblasts toward the wounded area remains undetectable until several days later. This "cell type traffic" regulation ensures proper healing of the wound, as disruptions of the regulation could either cause delay of wound healing or result in hypertrophic scars. TGFβ3 is the critical traffic controller that selectively halts migration of the dermal, but not epidermal, cells to ensure completion of wound re-epithelialization prior to wound remodeling. However, the mechanism of TGFβ3's anti-motility signaling has never been investigated. We report here that activated TbRII transmits the anti-motility signal of TGFβ3 in full to TbRI, since expression of the constitutively activated TbRITD mutant was sufficient to replace TGFβ3 to block PDGFbb-induced dermal fibroblast migration. Second, the three components of R-Smad complex are all required. Individual downregulation of Smad2, Smad3 or Smad4 prevented TGFβ3 from inhibiting dermal fibroblast migration. Third, Protein Kinase Array allowed us to identify the protein kinase A (PKA) as a specific downstream effector of R-Smads in dermal fibroblasts. Activation of PKA alone blocked PDGF-bb-induced dermal fibroblast migration, just like TGFβ3. Downregulation of PKA's catalytic subunit nullified the anti-motility signaling of TGFβ3. This is the first report on anti-motility signaling mechanism by TGFβ family cytokines. Significance of this finding is not only limited to wound healing but also to other human disorders, such as heart attack and cancer, where the diseased cells have often managed to avoid the anti-motility effect of TGFβ.
KW - Anti-motility
KW - Cell migration
KW - PKA
KW - TGFβ3
KW - Wound healing
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U2 - 10.1242/bio.20122246
DO - 10.1242/bio.20122246
M3 - Article
C2 - 23259050
AN - SCOPUS:84964843478
SN - 2046-6390
VL - 1
SP - 1169
EP - 1177
JO - Biology Open
JF - Biology Open
IS - 12
ER -