The Mammalian Cos2 Homolog Kif7 Plays an Essential Role in Modulating Hh Signal Transduction during Development

Abstract

The Hedgehog (Hh) signaling pathway regulates development in animals ranging from flies to humans. Although its framework is conserved, differences in pathway components have been reported. A kinesin-like protein, Costal2 (Cos2), plays a central role in the Hh pathway in flies. Knockdown of a zebrafish homolog of Cos2, Kif7, results in ectopic Hh signaling, suggesting that Kif7 acts primarily as a negative regulator of Hh signal transduction. However, in vitro analysis of the function of mammalian Kif7 and the closely related Kif27 has led to the conclusion that neither protein has a role in Hh signaling. Using Kif7 knockout mice, we demonstrate that mouse Kif7, like its zebrafish and Drosophila homologs, plays a role in transducing the Hh signal. We show that Kif7 accumulates at the distal tip of the primary cilia in a Hh-dependent manner. We also demonstrate a requirement for Kif7 in the efficient localization of Gli3 to cilia in response to Hh and for the processing of Gli3 to its repressor form. These results suggest a role for Kif7 in coordinating Hh signal transduction at the tip of cilia and preventing Gli3 cleavage into a repressor form in the presence of Hh.

Protecting the hedgerow: p53 and Hedgehog pathway interactions

“…Kif7 physically interacts with Gli proteins to control their stability and proteolysis and can act as both a positive or negative regulator of Hh signal transduction. [8][9][10] Activation of the Hh pathway induces Kif7 localization from the base of the cilia to the tip, suggesting a possible function for Kif7 as a ciliary motor. 9 In contrast, Kif27 is indicated in regulating the construction of the central pair apparatus of motile 9 + 2 cilia by the recruitment of Fu.…”

Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2

“…Taken together, these observations suggest Shh-induced phosphorylation of Smo is both necessary and sufficient to recruit Evc/Evc2, and the binding between Smo and Evc/Evc2 is mediated by Smo C-tail and is likely dependent on primary cilia. Several studies have shown that Kif7, the mammalian homolog of Drosophila Cos2, is involved in Hh signaling [24][25][26][27]. In Drosophila, Hh-induced Smo phosphorylation and conformational change promotes Smo/Cos2 association [20,21].…”

“…Activated Fu regulates both the activator and repressor form of Ci, likely by phosphorylating Cos2 and Sufu [18,[20][21][22][23]. Both Sufu and the mammalian homolog of Cos2, Kif7, are involved in Hh signaling [24][25][26][27][28]. By contrast, the mammalian homolog of Fu is not required for Hh signaling during development [29,30].…”

The Orphan G Protein-coupled Receptor Gpr175 (Tpra40) Enhances Hedgehog Signaling by Modulating cAMP Levels

“…Downstream of Smo, the SuFu⅐Gli complex (likely with Kif7) also accumulates in the cilium (13)(14)(15), and Gli phosphorylation by PKA is somehow inhibited, preventing cleavage of Gli-FL into Gli-R. There, the SuFu⅐Gli complex dissociates via unknown mechanism(s) (16), thereby leading to the activation of Gli-FL into Gli-A, which can activate Hh target gene transcription in the nucleus.…”