SIK phosphorylates and degrades Par3 to mediate tight junction disassembly during epithelial-mesenchymal transition

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Fältnamn	Indikatorer	Metadata
000		03349nam a2200349 4500
001		oai:DiVA.org:uu-152266
003		SwePub
008		110427s2011 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1522662 URI
040		a (SwePub)uu
041		a engb engb -1
042		9 SwePub
072	7	a vet2 swepub-contenttype
072	7	a ovr2 swepub-publicationtype
100	1	a Vanlandewijck, Michael,d 1982-u Uppsala universitet,Ludwiginstitutet för cancerforskning,TGF-ß signaling group4 aut0 (Swepub:uu)micva660
245	1 0	a SIK phosphorylates and degrades Par3 to mediate tight junction disassembly during epithelial-mesenchymal transition
264	1	c 2011
300		a 230 s.
338		a print2 rdacarrier
520		a Transforming growth factor β (TGFβ) is a multifunctional cytokine involved in homeostasis and disease during embryonic and adult life. TGFβ alters epithelial cell differentiation by inducing epithelial-mesenchymal transition (EMT), which involves disassembly of the epithelial adherens and tight junctions and downregulation of several junctional constituents.The mechanism by which TGFβ controls tight junction disassembly is poorly understood. We found that one of the newly identified gene targets of TGFβ, encodes for the serine/threonine kinase SIK (salt-inducible kinase), and controls tight junction assembly by this cytokine. We then identified a new phosphorylation substrate for SIK, the polarity complex protein Par3, which is an important regulator of tight junction assembly. SIK associates with Par3, phosphorylates serine 885 within the atypical protein kinase C-binding domain of Par3, and causes degradation of Par3. Mutation of serine 885 to alanine renders Par3 resistant to degradation induced by SIK. This mechanism is functionally important because both SIK and Par3 participate in the downregulation of tight junctions during EMT initiated by TGFβ signaling. Furthermore, we verified high level SIK expression in several different advanced and invasive human cancers. Notably, high SIK expression correlated with high level TGFβ/Smad signaling activity and with low or undetectable expression of Par3 in human breast cancers. Our model suggests that as the TGFβ signal progresses, SIK gets engaged in a concerted action that lowers signaling by its own receptor and initiates disassembly of the tight junction by acting directly on the polarity complex protein Par3.
520		a
653		a EMT
653		a Par3
653		a Signal transduction
653		a SIK
653		a TGFβ
700	1	a Lomnytska, Marta,d 1979-u Department of Oncology and Pathology, Karolinska Biomics Center, Karolinska Institute, Stockholm, Sweden4 aut0 (Swepub:uu)marlo829
700	1	a Busch, Christeru Uppsala universitet,Institutionen för immunologi, genetik och patologi4 aut0 (Swepub:uu)chrbusch
700	1	a Heldin, Carl-Henrik,d 1952-u Uppsala universitet,Ludwiginstitutet för cancerforskning4 aut0 (Swepub:uu)carlheld
700	1	a Moustakas, Aristidisu Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Ludwiginstitutet för cancerforskning4 aut0 (Swepub:uu)arimo287
710	2	a Uppsala universitetb Ludwiginstitutet för cancerforskning4 org
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-152266

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