STK11 is required for the normal program of ciliated cell differentiation in airways

The functional properties of mucosal surfaces are dependent on establishing the correct proportions of specialized epithelial cell types. Multiciliated cells (also known as ciliated cells) are evolutionarily conserved and functionally indispensable epithelial cells, as suggested by the link between ciliated cell dysfunction and chronic human disease. Ciliated cell differentiation is an ordered process that involves initial cell fate determination and multiciliogenesis. STK11, a serine/threonine kinase, has been reported to be downregulated in human diseases associated with ciliopathies and functions as a tumor suppressor. Here, we show that STK11 is a physiological factor for the normal program of ciliated cell differentiation by phosphorylating MARK3, which directly suppresses ERK1/2 mediated pRB inactivation. Loss of Stk11 in airway progenitors impairs the differentiation of ciliated cells in both embryonic and adult airways. Our study establishes that STK11/MARK3/ERK1/2 signaling cascade is a key regulator to integrate ciliated cell fate commitment and the subsequent process of multiciliogenesis.