RhoE Is Required for Keratinocyte Differentiation and Stratification

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2008 Oct 17

PMID 18923151

Citations 23

Authors

Timo Liebig

Jennifer Erasmus

Ruba Kalaji

Derek Davies

Gervaise Loirand

Anne Ridley

Vania M M Braga

Affiliations

Soon will be listed here.

Abstract

The molecular mechanism via which keratinocyte differentiation assembles multiple layers of cells (stratification) is poorly understood. We describe here a novel function of the Rho family member RhoE as a regulator of epidermal morphogenesis. RhoE protein levels are specifically and transiently up-regulated upon keratinocyte differentiation. RhoE up-regulation requires the activity of Rho kinase (ROCK) I, suggesting that both RhoE and ROCKI are important during keratinocyte differentiation. RhoE overexpression results in a striking enlargement of cell size and the number of stratified cells. In contrast, RhoE depletion induces hyperproliferation and delays initiation of keratinocyte differentiation. Interestingly, up-regulation of RhoE protein is seen primarily in basal, undifferentiated cells, in which commitment to differentiation and stratification takes place. RhoE activation in basal cells negatively modulates integrin adhesion, thereby facilitating detachment from the substratum and migration to form suprabasal layers. Thus, RhoE integrates two processes essential for keratinocyte differentiation and stratification: regulation of proliferative status and integrin adhesion.

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References

Hines M, Jin H, Wheelock M, Jensen P . Inhibition of cadherin function differentially affects markers of terminal differentiation in cultured human keratinocytes. J Cell Sci. 1999; 112 ( Pt 24):4569-79. DOI: 10.1242/jcs.112.24.4569. View

Nikolova E, Mitev V, Minner F, Deroanne C, Poumay Y . The inhibition of the expression of the small Rho GTPase Rac1 induces differentiation with no effect on cell proliferation in growing human adult keratinocytes. J Cell Biochem. 2007; 103(3):857-64. DOI: 10.1002/jcb.21455. View

Schmidt M, Goebeler M, Posern G, Feller S, Seitz C, Brocker E . Ras-independent activation of the Raf/MEK/ERK pathway upon calcium-induced differentiation of keratinocytes. J Biol Chem. 2000; 275(52):41011-7. DOI: 10.1074/jbc.M003716200. View

Wilde C, Chhatwal G, Schmalzing G, Aktories K, Just I . A novel C3-like ADP-ribosyltransferase from Staphylococcus aureus modifying RhoE and Rnd3. J Biol Chem. 2001; 276(12):9537-42. DOI: 10.1074/jbc.M011035200. View

Calautti E, Grossi M, Mammucari C, Aoyama Y, Pirro M, Ono Y . Fyn tyrosine kinase is a downstream mediator of Rho/PRK2 function in keratinocyte cell-cell adhesion. J Cell Biol. 2002; 156(1):137-48. PMC: 2173591. DOI: 10.1083/jcb.200105140. View

Van Aelst L, Symons M . Role of Rho family GTPases in epithelial morphogenesis. Genes Dev. 2002; 16(9):1032-54. DOI: 10.1101/gad.978802. View

Watt F . Role of integrins in regulating epidermal adhesion, growth and differentiation. EMBO J. 2002; 21(15):3919-26. PMC: 126145. DOI: 10.1093/emboj/cdf399. View

Garrod D, Merritt A, Nie Z . Desmosomal cadherins. Curr Opin Cell Biol. 2002; 14(5):537-45. DOI: 10.1016/s0955-0674(02)00366-6. View

Vaezi A, Bauer C, Vasioukhin V, Fuchs E . Actin cable dynamics and Rho/Rock orchestrate a polarized cytoskeletal architecture in the early steps of assembling a stratified epithelium. Dev Cell. 2002; 3(3):367-81. DOI: 10.1016/s1534-5807(02)00259-9. View

10.

McMullan R, Lax S, Robertson V, Radford D, Broad S, Watt F . Keratinocyte differentiation is regulated by the Rho and ROCK signaling pathway. Curr Biol. 2003; 13(24):2185-9. DOI: 10.1016/j.cub.2003.11.050. View

11.

Villalonga P, Guasch R, Riento K, Ridley A . RhoE inhibits cell cycle progression and Ras-induced transformation. Mol Cell Biol. 2004; 24(18):7829-40. PMC: 515038. DOI: 10.1128/MCB.24.18.7829-7840.2004. View

12.

Sugai M, Enomoto T, Hashimoto K, Matsumoto K, Matsuo Y, Ohgai H . A novel epidermal cell differentiation inhibitor (EDIN): purification and characterization from Staphylococcus aureus. Biochem Biophys Res Commun. 1990; 173(1):92-8. DOI: 10.1016/s0006-291x(05)81026-5. View

13.

Sugai M, Hashimoto K, Kikuchi A, Inoue S, Okumura H, Matsumoto K . Epidermal cell differentiation inhibitor ADP-ribosylates small GTP-binding proteins and induces hyperplasia of epidermis. J Biol Chem. 1992; 267(4):2600-4. View

14.

Wheelock M, Jensen P . Regulation of keratinocyte intercellular junction organization and epidermal morphogenesis by E-cadherin. J Cell Biol. 1992; 117(2):415-25. PMC: 2289421. DOI: 10.1083/jcb.117.2.415. View

15.

Jones P, Watt F . Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression. Cell. 1993; 73(4):713-24. DOI: 10.1016/0092-8674(93)90251-k. View

16.

Hodivala K, Watt F . Evidence that cadherins play a role in the downregulation of integrin expression that occurs during keratinocyte terminal differentiation. J Cell Biol. 1994; 124(4):589-600. PMC: 2119909. DOI: 10.1083/jcb.124.4.589. View

17.

Miyamoto S, Akiyama S, Yamada K . Synergistic roles for receptor occupancy and aggregation in integrin transmembrane function. Science. 1995; 267(5199):883-5. DOI: 10.1126/science.7846531. View

18.

BRAGA V, Hodivala K, Watt F . Calcium-induced changes in distribution and solubility of cadherins, integrins and their associated cytoplasmic proteins in human keratinocytes. Cell Adhes Commun. 1995; 3(3):201-15. DOI: 10.3109/15419069509081287. View

19.

BRAGA V, Machesky L, Hall A, Hotchin N . The small GTPases Rho and Rac are required for the establishment of cadherin-dependent cell-cell contacts. J Cell Biol. 1997; 137(6):1421-31. PMC: 2132529. DOI: 10.1083/jcb.137.6.1421. View

20.

Nobes C, Lauritzen I, Mattei M, Paris S, Hall A, Chardin P . A new member of the Rho family, Rnd1, promotes disassembly of actin filament structures and loss of cell adhesion. J Cell Biol. 1998; 141(1):187-97. PMC: 2132722. DOI: 10.1083/jcb.141.1.187. View