CTDNEP1:CNEP1R1 dephosphorylates LPIN

Stable Identifier
Reaction [transition]
Homo sapiens
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CTDNEP1:CNEP1R1 serine/threonine protein phosphatase complex consists of the catalytic subunit CTDNEP1 (Dullard) and the regulatory subunit CNEP1R1 (TMEM188) and is evolutionarily conserved from yeast to mammals (Kim et al. 2007, Han et al. 2012). CTDNEP1:CNEP1R1 and its yeast counterpart NEM1:SPO7 localize to the nuclear envelope and the endoplasmic reticulum membrane. CTDNEP1:CNEP1R1 dephosphorylates lipins (LPIN1, LPIN2 and LPIN3), which act as phosphatidate phosphatases, dephosphorylating phosphatidate (PA) and converting it to diacylglycerol (DAG). The yeast NEM1:SPO7 complex dephosphorylates yeast lipin orthologue PAH1 (SMP2, PAP1). CTDNEP1:CNEP1R1 shows a preference for the phosphorylated serine S106 of lipins. S106 phosphorylation is insulin-induced, and could be mediated by CDK1, as it is proline-directed (Wu et al. 2011). CDC28, a yeast homolog of CDK1, was shown to phosphorylate PAH1, while NEM1:SPO7 removes CDC28-introduced phosphate groups. Lipin phosphorylation regulates lipin localization, with phosphorylated lipins being soluble and dephosphorylated lipins being membrane-bound (Grimsey et al. 2008, Choi et al. 2011). The association of lipins with the nuclear envelope brings lipins in proximity to its substrate, PA, thereby enabling lipin catalytic activity (Karanasios et al. 2010). Catalytic activity of PAH1 regulates the morphology and dynamics of endoplasmic reticulum and nuclear membranes in yeast. In C. elegans and in human cell lines, lipin catalytic activity is needed for mitotic progression as it facilitates depolymerization of the nuclear lamina and nuclear envelope breakdown (Santos-Rosa et al. 2005, Kim et al. 2007, Gorjanacz et al. 2009, Golden et al. 2009, Choi et al. 2011, Mall et al. 2012).
Literature References
PubMed ID Title Journal Year
19494126 Inactivation of the C. elegans lipin homolog leads to ER disorganization and to defects in the breakdown and reassembly of the nuclear envelope

Liu, J, Cohen-Fix, O, Golden, A

J. Cell. Sci. 2009
22986494 Mitotic lamin disassembly is triggered by lipid-mediated signaling

Mall, M, Davidson, IF, Walter, T, Ellenberg, J, Nga Ly-Hartig, TB, Mattaj, IW, Gorjánácz, M

J. Cell Biol. 2012
19494125 Lipin is required for efficient breakdown of the nuclear envelope in Caenorhabditis elegans

Mattaj, IW, Gorjánácz, M

J. Cell. Sci. 2009
15889145 The yeast lipin Smp2 couples phospholipid biosynthesis to nuclear membrane growth

Leung, J, Santos-Rosa, H, Grimsey, N, Siniossoglou, S, Peak-Chew, S

EMBO J. 2005
17420445 A conserved phosphatase cascade that regulates nuclear membrane biogenesis

Kim, Y, Wiley, SE, Lawrence, JC, Gentry, MS, Harris, TE, Dixon, JE

Proc. Natl. Acad. Sci. U.S.A. 2007
20876142 A phosphorylation-regulated amphipathic helix controls the membrane translocation and function of the yeast phosphatidate phosphatase

Carman, GM, Xu, Z, Siniossoglou, S, Karanasios, E, Han, GS

Proc. Natl. Acad. Sci. U.S.A. 2010
18694939 Temporal and spatial regulation of the phosphatidate phosphatases lipin 1 and 2

O'Hara, L, Rochford, JJ, Carman, GM, Grimsey, N, Siniossoglou, S, Han, GS

J Biol Chem 2008
21413788 Homo sapiens dullard protein phosphatase shows a preference for the insulin-dependent phosphorylation site of lipin1

Wu, R, Garland, M, Allen, KN, Dunaway-Mariano, D

Biochemistry 2011
21081492 Phosphorylation of phosphatidate phosphatase regulates its membrane association and physiological functions in Saccharomyces cerevisiae: identification of SER(602), THR(723), AND SER(744) as the sites phosphorylated by CDC28 (CDK1)-encoded cyclin-dependent kinase

Morgan, JM, Carman, GM, Su, WM, Choi, HS, Xu, Z, Siniossoglou, S, Karanasios, E, Han, GS

J. Biol. Chem. 2011
22134922 Nuclear envelope phosphatase 1-regulatory subunit 1 (formerly TMEM188) is the metazoan Spo7p ortholog and functions in the lipin activation pathway

Graham, M, Grishin, N, Han, S, Goodman, JM, Reue, K, Zhang, P, Crooke, R, Bahmanyar, S, Oegema, K, Dixon, JE

J. Biol. Chem. 2012
Catalyst Activity

protein serine/threonine phosphatase activity of CTDNEP1:CNEP1R1 [nuclear envelope]

Orthologous Events
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