Cell-specific expression of the transcriptional regulator RHAMM provides a timing mechanism that controls appropriate wound re-epithelialization

Cornelia Tolg, Muhan Liu, Katelyn Cousteils, Patrick Telmer, Khandakar Alam, Jenny Ma, Leslie Mendina, James B. McCarthy, Vincent L. Morris, Eva A. Turley

Research output: Contribution to journalArticlepeer-review


Prevention of aberrant cutaneous wound repair and appropriate regeneration of an intact and functional integument require the coordinated timing of fibroblast and keratinocyte migration. Here, we identified a mechanism whereby opposing cell-specific motogenic functions of a multifunctional intracellular and extracellular protein, the receptor for hyaluronan-mediated motility (RHAMM), coordinates fibroblast and keratinocyte migration speed and ensures appropriate timing of excisional wound closure. We found that, unlike in WT mice, in Rhammnull mice, keratinocyte migration initiates prematurely in the excisional wounds, resulting in wounds that have re-surfaced before the formation of normal granulation tissue, leading to a defective epidermal architecture. We also noted aberrant keratinocyte and fibroblast migration in the Rhamm-null mice, indicating that RHAMM suppresses keratinocyte motility but increases fibroblast motility. This cell context– dependent effect resulted from cell-specific regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) activation and expression of a RHAMM target gene encoding matrix metalloprotease 9 (MMP-9). In fibroblasts, RHAMM promoted ERK1/2 activation and MMP-9 expression, whereas in keratinocytes, RHAMM suppressed these activities. In keratinocytes, loss of RHAMM function or expression promoted epidermal growth factor receptor–regulated MMP-9 expression via ERK1/2, which resulted in cleavage of the ectodomain of the RHAMM partner protein CD44 and thereby increased keratinocyte motility. These results identify RHAMM as a key factor that integrates the timing of wound repair by controlling cell migration.

Original languageEnglish (US)
Pages (from-to)5427-5448
Number of pages22
JournalJournal of Biological Chemistry
Issue number16
StatePublished - Apr 17 2020

Bibliographical note

Funding Information:
This work was supported by Lawson Health Sciences Center discretionary fund (to E. T.), the Breast Cancer Society of Canada (to E. T.), and the Chair-man’s Fund in Cancer Research and the Elsa-Pardee Foundation (to J. B. M.). The authors declare that they have no conflicts of interest with the contents of this article.

Publisher Copyright:
© 2020 Tolg et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.

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