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Vol. 20, Issue 12, 2954-2962, June 15, 2009

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BPAG1e Maintains Keratinocyte Polarity through β4 Integrin–mediated Modulation of Rac 1 and Cofilin Activities

Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, IL 60611

Submitted January 16, 2009; Revised March 24, 2009; Accepted April 17, 2009
Monitoring Editor: Jean E. Schwarzbauer

6β4 integrin, a component of hemidesmosomes, also plays a role in keratinocyte migration via signaling through Rac1 to the actin-severing protein cofilin. Here, we tested the hypothesis that the β4 integrin-associated plakin protein, bullous pemphigoid antigen 1e (BPAG1e) functions as a scaffold for Rac1/cofilin signal transduction. We generated keratinocyte lines exhibiting a stable knockdown in BPAG1e expression. Knockdown of BPAG1e does not affect expression levels of other hemidesmosomal proteins, nor the amount of β4 integrin expressed at the cell surface. However, the amount of Rac1 associating with β4 integrin and the activity of both Rac1 and cofilin are significantly lower in BPAG1e-deficient cells compared with wild-type keratinocytes. In addition, keratinocytes deficient in BPAG1e exhibit loss of front-to-rear polarity and display aberrant motility. These defects are rescued by inducing expression of constitutively active Rac1 or active cofilin. These data indicate that the BPAG1e is required for efficient regulation of keratinocyte polarity and migration by determining the activation of Rac1.

Address correspondence to: Jonathan C.R. Jones (j-jones3{at}northwestern.edu)

Abbreviations used: FRAP, fluorescence recovery after photobleaching; FACS, fluorescent-activated cell sorting; HEK, human epidermal keratinocytes.