Phosphorylation of CLK2 at Serine 34 and Threonine 127 by AKT Controls Cell Survival after Ionizing Radiation

Nam, Sang Yong; Seo, Hyung Ho; Park, Hyung Sun; An, Sungkwan; Kim, Jiyoung; Yang, Kwang Hee; Kim, Cha Soon; Jeong, Mi‐Ae; Jin, Young-Woo

doi:10.1074/jbc.m110.122044

Cited by 39 publications

(39 citation statements)

References 33 publications

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“…We and others have previously shown that feeding increases CLK2 in insulin-sensitive tissues such as the liver (Nam et al, 2010; Rodgers et al, 2010; Rodgers et al, 2011; Tabata et al, 2014). In hepatocytes, CLK2 is directly phosphorylated by AKT and auto-phosphorylated at several residues, leading to stabilization of the protein (Nam et al, 2010; Rodgers et al, 2010).…”

Section: Discussionmentioning

confidence: 83%

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Adipose Tissue CLK2 Promotes Energy Expenditure during High-Fat Diet Intermittent Fasting

et al. 2017

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Summary A promising approach to treating obesity is to increase diet-induced thermogenesis in brown adipose tissue (BAT), but the regulation of this process remains unclear. Here, we find that CDC-like kinase 2 (CLK2) is expressed in BAT and upregulated upon refeeding. Mice lacking CLK2 in adipose tissue exhibit exacerbated obesity and decreased energy expenditure during high fat intermittent fasting. Additionally, tissue oxygen consumption and protein levels of UCP1 are reduced in CLK2-deficient BAT. Phosphorylation of CREB, a transcriptional activator of UCP1, is markedly decreased in BAT cells lacking CLK2 due to enhanced CREB dephosphorylation. Mechanistically, CREB dephosphorylation is rescued by inhibition of PP2A, a phosphatase that targets CREB. Our results suggest that CLK2 is a regulatory component of diet-induced thermogenesis in BAT through increased CREB-dependent expression of UCP1.

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Section: Discussionmentioning

confidence: 83%

“…In hepatocytes, CLK2 is directly phosphorylated by AKT and auto-phosphorylated at several residues, leading to stabilization of the protein (Nam et al, 2010; Rodgers et al, 2010). Our results suggest a similar mechanism of CLK2 activation in BAT.…”

Section: Discussionmentioning

confidence: 99%

Adipose Tissue CLK2 Promotes Energy Expenditure during High-Fat Diet Intermittent Fasting

et al. 2017

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“…In addition, we examined splice events in Capn3 , Sirt2 , Csda , Clk2 and Madd , which are reported to regulate cell viability414243444546. We did not observe missplicing of Ttn exon 9, Ttn exon 311, or Ttn exons 114–119, 121–124 or 171–183 in Mbnl1 ΔE2/ΔE2 hearts (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 88%

Loss of muscleblind-like 1 results in cardiac pathology and persistence of embryonic splice isoforms

Dixon

Choi

El‐Ghazali

et al. 2015

Sci Rep

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Cardiac dysfunction is a prominent cause of mortality in myotonic dystrophy I (DM1), a disease where expanded CUG repeats bind and disable the muscleblind-like family of splice regulators. Deletion of muscleblind-like 1 (Mbnl1ΔE2/ΔE2) in 129 sv mice results in QRS, QTc widening, bundle block and STc narrowing at 2–4 months of age. With time, cardiac function deteriorates further and at 6 months, decreased R wave amplitudes, sinus node dysfunction, cardiac hypertrophy, interstitial fibrosis, multi-focal myocardial fiber death and calcification manifest. Sudden death, where no end point illness is overt, is observed at a median age of 6.5 and 4.8 months in ~67% and ~86% of male and female Mbnl1ΔE2/ΔE2 mice, respectively. Mbnl1 depletion results in the persistence of embryonic splice isoforms in a network of cardiac RNAs, some of which have been previously implicated in DM1, regulating sodium and calcium currents, Scn5a, Junctin, Junctate, Atp2a1, Atp11a, Cacna1s, Ryr2, intra and inter cellular transport, Clta, Stx2, Tjp1, cell survival, Capn3, Sirt2, Csda, sarcomere and cytoskeleton organization and function, Trim55, Mapt, Pdlim3, Pdlim5, Sorbs1, Sorbs2, Fhod1, Spag9 and structural components of the sarcomere, Myom1, Tnnt2, Zasp. Thus this study supports a key role for Mbnl1 loss in the initiation of DM1 cardiac disease.

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“…Finally, CLK2 is a negative regulator of AKT activity via phosphorylating and activating PP2A that leads to dephosphorylation of AKT (59,61). At the same time, CLK2 itself is activated by phosphorylation by AKT following ionizing radiation (62). Thus, CLK2 is both upstream and downstream of AKT forming a self-regulatory loop.…”

Section: Discussionmentioning

confidence: 99%

CLK2 Is an Oncogenic Kinase and Splicing Regulator in Breast Cancer

et al. 2015

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Genetically activated kinases have been attractive therapeutic targets in cancer due to the relative ease of developing tumorspecific treatment strategies for them. To discover novel putative oncogenic kinases, we identified 26 genes commonly amplified and overexpressed in breast cancer and subjected them to a lentiviral shRNA cell viability screen in a panel of breast cancer cell lines. Here, we report that CLK2, a kinase that phosphorylates SR proteins involved in splicing, acts as an oncogene in breast cancer. Deregulated alternative splicing patterns are commonly observed in human cancers but the underlying mechanisms and functional relevance are still largely unknown. CLK2 is amplified and overexpressed in a significant fraction of breast tumors. Downregulation of CLK2 inhibits breast cancer growth in cell culture and in xenograft models and it enhances cell migration and invasion. Loss of CLK2 in luminal breast cancer cells leads to the upregulation of epithelial-to-mesenchymal transition (EMT)-related genes and a switch to mesenchymal splice variants of several genes, including ENAH (MENA). These results imply that therapeutic targeting of CLK2 may be used to modulate EMT splicing patterns and to inhibit breast tumor growth. Cancer Res; 75(7); 1516-26.Ó2015 AACR.

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Phosphorylation of CLK2 at Serine 34 and Threonine 127 by AKT Controls Cell Survival after Ionizing Radiation

Cited by 39 publications

References 33 publications

Adipose Tissue CLK2 Promotes Energy Expenditure during High-Fat Diet Intermittent Fasting

Adipose Tissue CLK2 Promotes Energy Expenditure during High-Fat Diet Intermittent Fasting

Loss of muscleblind-like 1 results in cardiac pathology and persistence of embryonic splice isoforms

CLK2 Is an Oncogenic Kinase and Splicing Regulator in Breast Cancer

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