Dual function of UNC-51-like kinase 3 (Ulk3) in the Sonic hedgehog signaling pathway.
The Sonic hedgehog (Shh) signaling pathway controls a variety of developmental processes and is implicated in tissue homeostasis maintenance and neurogenesis in adults. Recently, we identified Ulk3 as an active kinase able to positively regulate Gli proteins, mediators of the Shh signaling in mammals. Here, we provide several lines of evidence that Ulk3 participates in the transduction of the Shh signal also independently of its kinase activity. We demonstrate that Ulk3 through its kinase domain interacts with Suppressor of Fused (Sufu), a protein required for negative regulation of Gli proteins. Sufu blocks Ulk3 autophosphorylation and abolishes its ability to phosphorylate and positively regulate Gli proteins. We show that Shh signaling destabilizes the Sufu-Ulk3 complex and induces the release of Ulk3. We demonstrate that the Sufu-Ulk3 complex, when co-expressed with Gli2, promotes generation of the Gli2 repressor form, and that reduction of the Ulk3 mRNA level in Shh-responsive cells results in higher potency of the cells to transmit the Shh signal. Our data suggests a dual function of Ulk3 in the Shh signal transduction pathway and propose an additional way of regulating Gli proteins by Sufu, through binding to and suppression of Ulk3.
Maloverjan
Alla
A
Department of Gene Technology, Institute of Clinical Medicine, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia.
Piirsoo
Marko
M
Kasak
Lagle
L
Peil
Lauri
L
Østerlund
Torben
T
Kogerman
Priit
P
D000818:Animals; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1
C400551:GLI1 protein, human; C498520:Gli1 protein, mouse; C498521:Gli1 protein, rat; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D046912:Multiprotein Complexes; D012333:RNA, Messenger; D012097:Repressor Proteins; C509239:SHH protein, human; C490764:SUFU protein, human; C465570:Shh protein, mouse; C546888:Shh protein, rat; C490763:Sufu protein, mouse; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D017346:Protein Serine-Threonine Kinases; C547386:ULK3 protein, human