Group:MUZIC:Synaptopodin

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Synaptopodin

Introduction

Synaptopodin, a protein encoded by the gene SYNPO,and represents a novel kind of proline-rich, actin-associated protein that may play a role in modulating actin-based shape and motility of dendritic spines and podocyte foot processes and in muscle cells is exclusively expressed in terminally differentiated skeletal muscle cells, where is colocalized with alpha-actinin and filamin C in the Z-disc. Either the founding member of a novel class of actin-associated proteins and also expressed in the brain, where it is found at the postsynaptic density and the spine apparatus in a subset of telencephalic neurons. In both brain and kidney, in vivo and in vitro, synaptopodin gene expression is differentiation dependent [1] [2]. Synaptopodin is either a member of the podin family, where we can find myopodin, present in avian smooth muscle (Leinweber et al. 1999)[3] heart and skeletal muscle (myopodin, genethonin-2, synaptopodin 2 or fesselin) (Weins et al. 2001)[4], and also the third member of the synaptopodin family of proteins, the synaptopodin 2-like protein is found in heart and skeletal muscle tissue and is better known under the names tritopodin (Claeys et al. 2009)[5] or CHAP (Beqqali et al. 2010)[6].

Sequence annotation

The protein KIBRA localized in podocytes directly bind to synaptopodin via the WW domains. The long variant of synaptopodin (903 aa) that is expressed in podocytes contains two internal PPxY sites, two PEST sequences, an actin-binding domain, and four α-actinin–binding regions (Duning et al. 2008)[7].

Synaptopodin exist in three different isoforms produced by alternative splicing of the N- and C-terminal exons.
Synaptopodin exist in three different isoforms produced by alternative splicing of the N- and C-terminal exons.

Structure

There is no structure related for this protein.

Function and interactions

The high degree of sequence similarity between the three members of the podin family in defined regions suggests analog binding properties. Indeed, biochemical studies revealed that all podin proteins interact with the Ig-domains 20-21 of filamin C. Similar to the situation in synaptopodin interaction studies showed that alpha-actinin binds also myopodin and tritopodin at multiple binding sites.(Linnemann et al. 2010)[8].Synaptopodin seems to be essential for the formation of spine apparatuses in spines of telencephalic neurons, which is involved in synaptic plasticity. synaptopodin is essential for the integrity of the podocyte actin cytoskeleton and for the regulation of podocyte cell migration [9]. Postictal upregulation of Synaptopodin mRNA levels in target cell populations of limbic epilepsy-elicited damage and subsequent Synaptopodin protein expression largely co-localized with remodeling processes as demonstrated by mossy fiber sprouting [10].

Pathology

Members of the podin family have been implicated in cancers. Synaptopodin 2 (myopodin) is expressed primarily in nuclei of proliferating myoblast cells. Cytoplasmic Synaptopodin 2 appears within hours of differentiation of myoblasts into myotubes and is found in Z-lines of mature myotubes. Like myopodin, synaptopodin associates with actin and appears to display actin-bundling activity, where is frequently absent in invasive prostate cancer and may serve as a prognostic marker for prostate cancers. (Weins et al. 2001)[11]. There is another level of complexity regarding the role of actin bundling proteins in cancer. Metastasis requires cell motility, a property normally associated with plasticity of actin filaments. However, there is ample evidence that bundling of actin filaments is a prerequisite for formation of invadosomes. Elevated levels of some actin bundling proteins are associated with more aggressive cancer phenotypes.(Iguchi et al. 2009)[12].

References

  1. ↑ Mundel P, Heid HW, Mundel TM, Kruger M, Reiser J, Kriz W. Synaptopodin: an actin-associated protein in telencephalic dendrites and renal podocytes. J Cell Biol. 1997 Oct 6;139(1):193-204. PMID:9314539
  2. ↑ Deller T, Merten T, Roth SU, Mundel P, Frotscher M. Actin-associated protein synaptopodin in the rat hippocampal formation: localization in the spine neck and close association with the spine apparatus of principal neurons. J Comp Neurol. 2000 Mar 6;418(2):164-81. PMID:10701442
  3. ↑ Leinweber BD, Fredricksen RS, Hoffman DR, Chalovich JM. Fesselin: a novel synaptopodin-like actin binding protein from muscle tissue. J Muscle Res Cell Motil. 1999 Aug;20(5-6):539-45. PMID:10555072
  4. ↑ Weins A, Schwarz K, Faul C, Barisoni L, Linke WA, Mundel P. Differentiation- and stress-dependent nuclear cytoplasmic redistribution of myopodin, a novel actin-bundling protein. J Cell Biol. 2001 Oct 29;155(3):393-404. Epub 2001 Oct 22. PMID:11673475 doi:10.1083/jcb.200012039
  5. ↑ Claeys KG, van der Ven PF, Behin A, Stojkovic T, Eymard B, Dubourg O, Laforet P, Faulkner G, Richard P, Vicart P, Romero NB, Stoltenburg G, Udd B, Fardeau M, Voit T, Furst DO. Differential involvement of sarcomeric proteins in myofibrillar myopathies: a morphological and immunohistochemical study. Acta Neuropathol. 2009 Mar;117(3):293-307. Epub 2009 Jan 17. PMID:19151983 doi:10.1007/s00401-008-0479-7
  6. ↑ Beqqali A, Monshouwer-Kloots J, Monteiro R, Welling M, Bakkers J, Ehler E, Verkleij A, Mummery C, Passier R. CHAP is a newly identified Z-disc protein essential for heart and skeletal muscle function. J Cell Sci. 2010 Apr 1;123(Pt 7):1141-50. Epub 2010 Mar 9. PMID:20215401 doi:10.1242/jcs.063859
  7. ↑ Duning K, Schurek EM, Schluter M, Bayer M, Reinhardt HC, Schwab A, Schaefer L, Benzing T, Schermer B, Saleem MA, Huber TB, Bachmann S, Kremerskothen J, Weide T, Pavenstadt H. KIBRA modulates directional migration of podocytes. J Am Soc Nephrol. 2008 Oct;19(10):1891-903. doi: 10.1681/ASN.2007080916. Epub, 2008 Jul 2. PMID:18596123 doi:10.1681/ASN.2007080916
  8. ↑ Linnemann A, van der Ven PF, Vakeel P, Albinus B, Simonis D, Bendas G, Schenk JA, Micheel B, Kley RA, Furst DO. The sarcomeric Z-disc component myopodin is a multiadapter protein that interacts with filamin and alpha-actinin. Eur J Cell Biol. 2010 Sep;89(9):681-92. Epub 2010 May 31. PMID:20554076 doi:10.1016/j.ejcb.2010.04.004
  9. ↑ Asanuma K, Yanagida-Asanuma E, Faul C, Tomino Y, Kim K, Mundel P. Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling. Nat Cell Biol. 2006 May;8(5):485-91. Epub 2006 Apr 16. PMID:16622418 doi:10.1038/ncb1400
  10. ↑ Roth SU, Sommer C, Mundel P, Kiessling M. Expression of synaptopodin, an actin-associated protein, in the rat hippocampus after limbic epilepsy. Brain Pathol. 2001 Apr;11(2):169-81. PMID:11303792
  11. ↑ Weins A, Schwarz K, Faul C, Barisoni L, Linke WA, Mundel P. Differentiation- and stress-dependent nuclear cytoplasmic redistribution of myopodin, a novel actin-bundling protein. J Cell Biol. 2001 Oct 29;155(3):393-404. Epub 2001 Oct 22. PMID:11673475 doi:10.1083/jcb.200012039
  12. ↑ Iguchi T, Aishima S, Umeda K, Sanefuji K, Fujita N, Sugimachi K, Gion T, Taketomi A, Maehara Y, Tsuneyoshi M. Fascin expression in progression and prognosis of hepatocellular carcinoma. J Surg Oncol. 2009 Dec 1;100(7):575-9. doi: 10.1002/jso.21377. PMID:19697358 doi:10.1002/jso.21377

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