The Catalytically Inactive Tyrosine Phosphatase HD-PTP/PTPN23 is a Novel Regulator of SMN Complex Localization

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2014 Nov 14

PMID 25392300

Citations 17

Authors

Alma Husedzinovic

Beate Neumann

Jurgen Reymann

Stefanie Draeger-Meurer

Ashwin Chari

Holger Erfle

Utz Fischer

Oliver J Gruss

Affiliations

Soon will be listed here.

Abstract

The survival motor neuron (SMN) complex fulfils essential functions in the assembly of snRNPs, which are key components in the splicing of pre-mRNAs. Little is known about the regulation of SMN complex activity by posttranslational modification despite its complicated phosphorylation pattern. Several phosphatases had been implicated in the regulation of SMN, including the nuclear phosphatases PPM1G and PP1γ. Here we systematically screened all human phosphatase gene products for a regulatory role in the SMN complex. We used the accumulation of SMN in Cajal bodies of intact proliferating cells, which actively assemble snRNPs, as a readout for unperturbed SMN complex function. Knockdown of 29 protein phosphatases interfered with SMN accumulation in Cajal bodies, suggesting impaired SMN complex function, among those the catalytically inactive, non-receptor-type tyrosine phosphatase PTPN23/HD-PTP. Knockdown of PTPN23 also led to changes in the phosphorylation pattern of SMN without affecting the assembly of the SMN complex. We further show interaction between SMN and PTPN23 and document that PTPN23, like SMN, shuttles between nucleus and cytoplasm. Our data provide the first comprehensive screen for SMN complex regulators and establish a novel regulatory function of PTPN23 in maintaining a highly phosphorylated state of SMN, which is important for its proper function in snRNP assembly.

Citing Articles

Generative modeling for RNA splicing predictions and design.

Wu D, Maus N, Jha A, Yang K, Wales-McGrath B, Jewell S bioRxiv. 2025; .

PMID: 39896553 PMC: 11785043. DOI: 10.1101/2025.01.20.633986.

PTPN23-dependent activation of PI3KC2α is a therapeutic vulnerability of BRAF-mutant cancers.

He Y, Li W, Zhang M, Wang H, Lin P, Yu Y J Exp Med. 2025; 222(3.

PMID: 39841180 PMC: 11753290. DOI: 10.1084/jem.20241147.

PPM1G and its diagnostic, prognostic and therapeutic potential in HCC (Review).

Zhang X, Wang H, Yuan Y, Zhang J, Yang J, Zhang L Int J Oncol. 2024; 65(5).

PMID: 39329206 PMC: 11436262. DOI: 10.3892/ijo.2024.5697.

SHP2 as a primordial epigenetic enzyme expunges histone H3 pTyr-54 to amend androgen receptor homeostasis.

Chouhan S, Sridaran D, Weimholt C, Luo J, Li T, Hodgson M Nat Commun. 2024; 15(1):5629.

PMID: 38965223 PMC: 11224269. DOI: 10.1038/s41467-024-49978-4.

Genetic Variants in Protein Tyrosine Phosphatase Non-Receptor Type 23 Are Responsible for Mesiodens Formation.

Adisornkanj P, Chanprasit R, Eliason S, Fons J, Intachai W, Tongsima S Biology (Basel). 2023; 12(3).

PMID: 36979085 PMC: 10045488. DOI: 10.3390/biology12030393.

References

Sleeman J, Lamond A . Newly assembled snRNPs associate with coiled bodies before speckles, suggesting a nuclear snRNP maturation pathway. Curr Biol. 1999; 9(19):1065-74. DOI: 10.1016/s0960-9822(99)80475-8. View

Burghes A, Beattie C . Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick?. Nat Rev Neurosci. 2009; 10(8):597-609. PMC: 2853768. DOI: 10.1038/nrn2670. View

Meister G, Buhler D, Laggerbauer B, Zobawa M, Lottspeich F, Fischer U . Characterization of a nuclear 20S complex containing the survival of motor neurons (SMN) protein and a specific subset of spliceosomal Sm proteins. Hum Mol Genet. 2000; 9(13):1977-86. DOI: 10.1093/hmg/9.13.1977. View

Toyooka S, Ouchida M, Jitsumori Y, Tsukuda K, Sakai A, Nakamura A . HD-PTP: A novel protein tyrosine phosphatase gene on human chromosome 3p21.3. Biochem Biophys Res Commun. 2000; 278(3):671-8. DOI: 10.1006/bbrc.2000.3870. View

Stark H, Dube P, Luhrmann R, Kastner B . Arrangement of RNA and proteins in the spliceosomal U1 small nuclear ribonucleoprotein particle. Nature. 2001; 409(6819):539-42. DOI: 10.1038/35054102. View

Meister G, Buhler D, Pillai R, Lottspeich F, Fischer U . A multiprotein complex mediates the ATP-dependent assembly of spliceosomal U snRNPs. Nat Cell Biol. 2001; 3(11):945-9. DOI: 10.1038/ncb1101-945. View

Cohen P . Protein phosphatase 1--targeted in many directions. J Cell Sci. 2002; 115(Pt 2):241-56. DOI: 10.1242/jcs.115.2.241. View

Darzacq X, Jady B, Verheggen C, Kiss A, Bertrand E, Kiss T . Cajal body-specific small nuclear RNAs: a novel class of 2'-O-methylation and pseudouridylation guide RNAs. EMBO J. 2002; 21(11):2746-56. PMC: 126017. DOI: 10.1093/emboj/21.11.2746. View

Kiss A, Jady B, Darzacq X, Verheggen C, Bertrand E, Kiss T . A Cajal body-specific pseudouridylation guide RNA is composed of two box H/ACA snoRNA-like domains. Nucleic Acids Res. 2002; 30(21):4643-9. PMC: 135803. DOI: 10.1093/nar/gkf592. View

10.

Pellizzoni L, Yong J, Dreyfuss G . Essential role for the SMN complex in the specificity of snRNP assembly. Science. 2002; 298(5599):1775-9. DOI: 10.1126/science.1074962. View

11.

Carnegie G, Sleeman J, Morrice N, Hastie C, Peggie M, Philp A . Protein phosphatase 4 interacts with the Survival of Motor Neurons complex and enhances the temporal localisation of snRNPs. J Cell Sci. 2003; 116(Pt 10):1905-13. DOI: 10.1242/jcs.00409. View

12.

Schaffert N, Hossbach M, Heintzmann R, Achsel T, Luhrmann R . RNAi knockdown of hPrp31 leads to an accumulation of U4/U6 di-snRNPs in Cajal bodies. EMBO J. 2004; 23(15):3000-9. PMC: 514917. DOI: 10.1038/sj.emboj.7600296. View

13.

Narayanan U, Achsel T, Luhrmann R, Matera A . Coupled in vitro import of U snRNPs and SMN, the spinal muscular atrophy protein. Mol Cell. 2004; 16(2):223-34. DOI: 10.1016/j.molcel.2004.09.024. View

14.

Laemmli U . Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970; 227(5259):680-5. DOI: 10.1038/227680a0. View

15.

Wessel D, Flugge U . A method for the quantitative recovery of protein in dilute solution in the presence of detergents and lipids. Anal Biochem. 1984; 138(1):141-3. DOI: 10.1016/0003-2697(84)90782-6. View

16.

Kambach C, Walke S, Young R, Avis J, de La Fortelle E, Raker V . Crystal structures of two Sm protein complexes and their implications for the assembly of the spliceosomal snRNPs. Cell. 1999; 96(3):375-87. DOI: 10.1016/s0092-8674(00)80550-4. View

17.

Grimmler M, Bauer L, Nousiainen M, Korner R, Meister G, Fischer U . Phosphorylation regulates the activity of the SMN complex during assembly of spliceosomal U snRNPs. EMBO Rep. 2004; 6(1):70-6. PMC: 1299218. DOI: 10.1038/sj.embor.7400301. View

18.

Neumann B, Held M, Liebel U, Erfle H, Rogers P, Pepperkok R . High-throughput RNAi screening by time-lapse imaging of live human cells. Nat Methods. 2006; 3(5):385-90. DOI: 10.1038/nmeth876. View

19.

Lemm I, Girard C, Kuhn A, Watkins N, Schneider M, Bordonne R . Ongoing U snRNP biogenesis is required for the integrity of Cajal bodies. Mol Biol Cell. 2006; 17(7):3221-31. PMC: 1483051. DOI: 10.1091/mbc.e06-03-0247. View

20.

Stanek D, Neugebauer K . The Cajal body: a meeting place for spliceosomal snRNPs in the nuclear maze. Chromosoma. 2006; 115(5):343-54. DOI: 10.1007/s00412-006-0056-6. View