The GEF Bcr activates RhoA/MAL signaling to promote keratinocyte differentiation via desmoglein-1.
Although much is known about signaling factors downstream of Rho GTPases that contribute to epidermal differentiation, little is known about which upstream regulatory proteins (guanine nucleotide exchange factors [GEFs] or GTPase-activating proteins [GAPs]) are involved in coordinating Rho signaling in keratinocytes. Here we identify the GEF breakpoint cluster region (Bcr) as a major upstream regulator of RhoA activity, stress fibers, and focal adhesion formation in keratinocytes. Loss of Bcr reduced expression of multiple markers of differentiation (such as desmoglein-1 [Dsg1], keratin-1, and loricrin) and abrogated MAL/SRF signaling in differentiating keratinocytes. We further demonstrated that loss of Bcr or MAL reduced levels of Dsg1 mRNA in keratinocytes, and ectopic expression of Dsg1 rescued defects in differentiation seen upon loss of Bcr or MAL signaling. Taken together, these data identify the GEF Bcr as a regulator of RhoA/MAL signaling in keratinocytes, which in turn promotes differentiation through the desmosomal cadherin Dsg1.
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Adi D
AD
Dubash
Jennifer L
JL
Koetsier
Evangeline V
EV
Amargo
Nicole A
NA
Najor
Robert M
RM
Harmon
Kathleen J
KJ
Green
D002454:Cell Differentiation; D045744:Cell Line, Tumor; D051183:Desmoglein 1 / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins / Q000378:metabolism*; D051562:Proto-Oncogene Proteins c-bcr / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D051183:Desmoglein 1; C569026:MAL protein, human; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D012333:RNA, Messenger; C066737:RHOA protein, human; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr; D020742:rhoA GTP-Binding Protein