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The Hedgehog (Hh) family of secreted proteins governs cell growth and patterning in animal development. The Hh signal is transduced by the seven-transmembrane protein Smoothened (Smo); however, the mechanism by which Smo is regulated remains largely unknown. Here we show that protein kinase A (PKA) and casein kinase I (CKI) regulate Smo cell-surface(More)
The Drosophila protein Shaggy (Sgg, also known as Zeste-white3, Zw3) and its vertebrate orthologue glycogen synthase kinase 3 (GSK3) are inhibitory components of the Wingless (Wg) and Wnt pathways. Here we show that Sgg is also a negative regulator in the Hedgehog (Hh) pathway. In Drosophila, Hh acts both by blocking the proteolytic processing of(More)
Hedgehog (Hh) proteins control animal development by regulating the Gli/Ci family of transcription factors. In Drosophila, Hh counteracts phosphorylation by PKA, GSK3, and CKI to prevent Cubitus interruptus (Ci) processing through unknown mechanisms. Here, we show that these kinases physically interact with the kinesin-like protein Costal2 (Cos2) to control(More)
In a genetic screen for mutations that restrict cell growth and organ size, we identified a new tumor suppressor gene, dMST, which encodes the Drosophila homolog of the mammalian Ste20 kinase family members MST1 and MST2. Loss-of-function mutations in dMST result in overgrown tissues containing more cells of normal size. dMST mutant cells exhibit elevated(More)
The Hedgehog (Hh) family of secreted proteins controls many aspects of growth and patterning in animal development. The seven-transmembrane protein Smoothened (Smo) transduces the Hh signal in both vertebrates and invertebrates; however, the mechanism of its action remains unknown. We found that Smo lacking its C-terminal tail (C-tail) is inactive, whereas(More)
Mutations in fused in sarcoma (FUS) have been reported to cause a subset of familial amyotrophic lateral sclerosis (ALS) cases. Wild-type FUS is mostly localized in the nuclei of neurons, but the ALS mutants are partly mislocalized in the cytoplasm and can form inclusions. We demonstrate that the C-terminal 32 amino acid residues of FUS constitute an(More)
Amyotrophic lateral sclerosis (ALS) is progressive neurodegenerative disease characterized by the loss of motor function. Several ALS genes have been identified as their mutations can lead to familial ALS, including the recently reported RNA-binding protein fused in sarcoma (Fus). However, it is not clear how mutations of Fus lead to motor neuron(More)
The seven transmembrane protein Smoothened (Smo) is a critical component of the Hedgehog (Hh) signaling pathway and is regulated by phosphorylation, dimerization, and cell-surface accumulation upon Hh stimulation. However, it is not clear how Hh regulates Smo accumulation on the cell surface or how Hh regulates the intracellular trafficking of Smo. In(More)
Hedgehog (Hh) proteins govern animal development by regulating the Gli/Ci family of transcription factors. In Drosophila, Hh signaling blocks proteolytic processing of full-length Ci to generate a truncated repressor form. Ci processing requires sequential phosphorylation by PKA, GSK3, and a casein kinase I (CKI) family member(s). Here we show that(More)
The seven-transmembrane protein Smoothened (Smo) and Zn-finger transcription factor Ci/Gli are crucial components in Hedgehog (Hh) signal transduction that mediates a variety of processes in animal development. In Drosophila, multiple kinases have been identified to regulate Hh signaling by phosphorylating Smo and Ci; however, the phosphatase(s) involved(More)