Sonic Hedgehog (Shh) signaling pathway is implicated in various developmental and postnatal processes. Much of the current knowledge about the mechanisms of Shh signal transduction in vertebrates comes from the investigations of the respective pathway in fruit fly Drosophila melanogaster. In Drosophila, serine/threonine kinase fused is involved in all aspects of regulation of the Hh-dependent transcription factor cubitus interruptus possessing both catalytic and regulatory functions. Two proteins, Stk36 and Ulk3, share similarity with fu and have been suggested as mammalian fu homologues. However, in vivo data clarify that Stk36 is not required for embryonic development in mice and participates in Shh-independent genesis of motile cilia. Even if Stk36 is associated with any pathological or physiological aspect of postnatal Shh signaling in mammals, it has perhaps only regulatory functions since its catalytic activity seems to be lost during evolution. In contrast to Stk36, Ulk3 is an active kinase. In non-stimulated cells, Ulk3 catalytic activity is blocked, and it is involved in negative control of Gli proteins, mediators of Shh signaling. In response to Shh, Ulk3 positively regulates Gli proteins by directly phosphorylating them. Thus, Ulk3 is able to recapitulate both positive and negative roles of fu in vitro. However, Ulk3 functioning in vivo remains to be investigated.
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