![]() ![]() On the basis of correlated biochemical changes it has been speculated that Fu modifies Su(fu) function by direct phosphorylation and that Fu is activated by a process involving Fu phosphorylation ( Hooper and Scott, 2005). Fu is thought only to antagonize Su(fu) because loss of Su(fu) substantially restores Hh signaling impaired by genetic inactivation of Fu kinase ( Preat, 1992). Smo also activates Fu, which can bind Smo, Cos2 and Su(fu), leading to increased activity of stabilized Ci-155 ( Hooper and Scott, 2005). In Drosophila, Smo contacts Cos2 directly and is thought to inhibit Ci-155 processing by reducing the association of Cos2 with Ci-155 or with PKA, GSK3 and CK1 ( Ruel et al., 2003 Zhang et al., 2005). However, there is no known direct contact between Smo and SUFU and no mechanistic model that connects the two. In mice, loss of SUFU produces strong ectopic Hh target gene induction, provoking the suggestion that Hh signaling requires Smo to antagonize the silencing of Gli activators by SUFU ( Wilson and Chuang, 2010). Conversely, many additional proteins associated with the regulation of the primary cilium are essential for normal Hh signaling in mice, but not in flies ( Goetz and Anderson, 2010). However, mouse Fu appears to play no role, even though Fu has been implicated in Hh signaling in zebrafish ( Wilson and Chuang, 2010). The repressive binding partner, Suppressor of Fused (designated Su(fu) in flies and SUFU in mammals) is also conserved. In mice the same three protein kinases, Protein Kinase A (PKA), Glycogen Synthase Kinase 3 (GSK3) and Casein Kinase 1 (CK1), act analogously on Gli proteins together with a Cos2 ortholog, Kif7 to direct Gli ubiquitination and proteasome-mediated proteolysis ( Huangfu and Anderson, 2006 Wilson and Chuang, 2010). In Drosophila this involves a kinesin-family protein, Costal 2 (Cos2), three protein kinases that phosphorylate Ci-155 to promote its processing to Ci-75, a repressive binding partner of Ci-155 and a fourth protein kinase, Fused (Fu). Precisely how Smo regulates Ci is unresolved. This basic scheme was found also to apply to vertebrates, in which Ci has multiple paralogs called Gli proteins ( Huangfu and Anderson, 2006 Wilson and Chuang, 2010). When Hh binds Ptc, Smo becomes active, Ci-155 processing is blocked and Ci-155 activates Hh target genes. When Hh is absent, its receptor Patched (Ptc) prevents the accumulation and activity of the seven trans-membrane protein Smoothened (Smo), full-length Ci-155 is retained in the cytoplasm and slowly processed to a shorter product, Ci-75, which accumulates in the nucleus, binds DNA and represses Hh target genes. Hh signaling was studied first and with the greatest resolution in a physiological setting in Drosophila, revealing the pivotal role of a single transcription factor, Cubitus interruptus (Ci) ( Hooper and Scott, 2005). Understanding exactly how Hh signals are transduced is therefore essential to appreciate how signaling is integrated into the organized development and regulation of a complex organism, and in order to diagnose and devise therapies for a variety of human genetic conditions. ![]() In this model, Smo acts like many transmembrane receptors associated with cytoplasmic kinases, such that pathway activation is mediated by kinase oligomerization and trans-phosphorylation.Ĭhanges in cell fate and proliferation instructed by extracellular Hedgehog (Hh) signaling molecules are critical in development, tissue maintenance and cancer ( Ingham and McMahon, 2001 Jiang and Hui, 2008). Autoactivation primes Fu for additional CK1-dependent phosphorylation, which further enhances kinase activity. We propose that Smo/Cos2 interactions stimulate Fu autoactivation by concentrating Fu at the membrane. ![]() Activated Fu can recapitulate a full Hh response, stabilizing full-length Ci via Cos2 phosphorylation and activating full-length Ci by antagonizing Su(fu) and by other mechanisms. Here we show that the Fused (Fu) protein kinase is activated by Smo and Cos2 via Fu- and CK1-dependent phosphorylation. How Hh-induced activation of transmembrane Smoothened (Smo) proteins reverses Ci/Gli inhibition by Suppressor of Fused (SuFu) and kinesin-family protein (Cos2/Kif7) binding partners is a major unanswered question. In flies and mammals extracellular Hedgehog (Hh) molecules alter cell fates and proliferation by regulating the levels and activities of Ci/Gli family transcription factors. ![]()
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