Group:MUZIC:Myopodin: Difference between revisions

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Myopodin also binds to α-actinin via its spectrin repeats <ref> PMID:16450054 </ref>, <ref> PMID:20554076 </ref> . Myopodin may be generally involved in the organization and anchoring of actin in muscle cells and might be required for the correct localization of α-actinin. This hypothesis is supported by recent findings where myopodin expression precedes actin and α-actinin expression <ref> PMID:20554076 </ref>.
Myopodin also binds to α-actinin via its spectrin repeats <ref> PMID:16450054 </ref>, <ref> PMID:20554076 </ref> . Myopodin may be generally involved in the organization and anchoring of actin in muscle cells and might be required for the correct localization of α-actinin. This hypothesis is supported by recent findings where myopodin expression precedes actin and α-actinin expression <ref> PMID:20554076 </ref>.
A filamin-binding region was mapped to a fragment encompassing amino acids 240–521 of myopodin, i.e. a region that contains two of the previously described homology regions shared by myopodin and synaptopodin <ref> PMID:20554076 </ref>.
A filamin-binding region was mapped to a fragment encompassing amino acids 240–521 of myopodin, i.e. a region that contains two of the previously described homology regions shared by myopodin and synaptopodin <ref> PMID:20554076 </ref>.
The alternative transcription offers the possibility of expression of two isoforms of Myopodin, which probably differ in their binding properties for these PDZ binding domain detected, however, there is preliminary evidence that the PDZ binding domain from Myopodin interacts with the C terminal part of Synemin <ref> PMID:16631741 </ref>.
Through yeast two-hybrid analysis, was found the interaction between Myopodin and Zyxin both in vitro and in vivo and that this interaction leads to slower migration of prostate cancer cells and reduced invasiveness <ref> PMID:16885336 </ref>.
Through yeast two-hybrid analysis, was found the interaction between Myopodin and Zyxin both in vitro and in vivo and that this interaction leads to slower migration of prostate cancer cells and reduced invasiveness <ref> PMID:16885336 </ref>.
In cardiomyocytes, Myopodin forms a Z-disc signaling complex with α-Actinin, Calcineurin, Ca2+/calmodulin-dependent kinase II (CaMKII), Muscle-specific A-kinase anchoring protein, and Myomegalin. Calcineurin keeps Myopodin dephosphorylated preventing 14-3-3ß binding to myopodin. Upon activation of PKA/CaMKII or inhibition of Calcineurin, Myopodin undergoes phosphorylation, enabling its interaction with 14-3-3ß, which releases Myopodin from the Z-disc-anchoring proteins and induces its nuclear import. This novel intracellular signaling pathway suggests that changes in Z-disc dynamics may translate into compartmentalized signal transduction in the heart <ref> PMID:17923693 </ref>.
In cardiomyocytes, Myopodin forms a Z-disc signaling complex with α-Actinin, Calcineurin, Ca2+/calmodulin-dependent kinase II (CaMKII), Muscle-specific A-kinase anchoring protein, and Myomegalin. Calcineurin keeps Myopodin dephosphorylated preventing 14-3-3ß binding to myopodin. Upon activation of PKA/CaMKII or inhibition of Calcineurin, Myopodin undergoes phosphorylation, enabling its interaction with 14-3-3ß, which releases Myopodin from the Z-disc-anchoring proteins and induces its nuclear import. This novel intracellular signaling pathway suggests that changes in Z-disc dynamics may translate into compartmentalized signal transduction in the heart <ref> PMID:17923693 </ref>.

Revision as of 18:35, 18 July 2011

Prediction of the PDZ binding domain of Myopodin . Lambert et al. ESyPred3D:Prediction of Proteins 3D structures. Bioinformatics 2002)

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MYOPODINMYOPODIN

The protein myopodin (encoded by the gene SYNPO2[1]), is also called genethonin-2, synaptopodin-2, synaptopodin-like and fesselin; it was first described in 2001 by Weins et al., and shown to be widely expressed in striated- and smooth-muscle cells [1] [2]. At least six isoforms result from alternative splicing and the size of the resulting proteins varies between 76 kDa and 136 kDa; these variants show differential tissue distribution. The discrepancy between calculated molecular mass and apparent mobility in SDS-PAGE is at present still unclear, but might be due to post-translational modifications [3] [4] [5] [6] [7].

FunctionFunction

Myopodin is a dual compartment protein that redistributes between the nucleus and the cytoplasm in a differentiation-dependent and stress-induced fashion, and in addition displays actin-bundling activity [8]. In undifferentiated myoblasts, myopodin seems to be expressed preferentially in the nucleus and only weakly in the cytoplasm, whereas in differentiated myotubes, myopodin is incorporated into the Z-disc with no detectable nuclear expression, suggesting that myopodin may be involved in the regulation of myocyte differentiation [9]. Myopodin has also been identified as a tumor suppressor gene that is frequently deleted in aggressive prostate cancer [10]. Expression of myopodin protein suppresses both tumor growth and metastasis in vitro and in vivo [11].


500x


Myopodin InteractionsMyopodin Interactions

Actin was the first binding partner of myopodin to be identified. Actin binding was narrowed down to residues 410–563 of murine myopodin [12]. Myopodin also binds to α-actinin via its spectrin repeats [13], [14] . Myopodin may be generally involved in the organization and anchoring of actin in muscle cells and might be required for the correct localization of α-actinin. This hypothesis is supported by recent findings where myopodin expression precedes actin and α-actinin expression [15]. A filamin-binding region was mapped to a fragment encompassing amino acids 240–521 of myopodin, i.e. a region that contains two of the previously described homology regions shared by myopodin and synaptopodin [16]. Through yeast two-hybrid analysis, was found the interaction between Myopodin and Zyxin both in vitro and in vivo and that this interaction leads to slower migration of prostate cancer cells and reduced invasiveness [17]. In cardiomyocytes, Myopodin forms a Z-disc signaling complex with α-Actinin, Calcineurin, Ca2+/calmodulin-dependent kinase II (CaMKII), Muscle-specific A-kinase anchoring protein, and Myomegalin. Calcineurin keeps Myopodin dephosphorylated preventing 14-3-3ß binding to myopodin. Upon activation of PKA/CaMKII or inhibition of Calcineurin, Myopodin undergoes phosphorylation, enabling its interaction with 14-3-3ß, which releases Myopodin from the Z-disc-anchoring proteins and induces its nuclear import. This novel intracellular signaling pathway suggests that changes in Z-disc dynamics may translate into compartmentalized signal transduction in the heart [18].

File:Myopodin interaction with FLNC.jpg File:Model for the regulation of myopodin's subcellular localization in cardiac myocytes.jpg

PathologyPathology

Already in 2001 Lin et al showed that SYNPO2 gene exhibit frequently delations in aggresive prostata cancer [19]. Later analysis gave the evidence that Myopodin plays an important role as tumor suppressor, considering that in normal urothelium of the bladder Myopodin is localized in the cytoplasm and in the nucleus, however in mutated tissue of superficial and invasive bladder tumor is observed a reduced nuclear expression of Myopodin [20]. Furthermore the expression of Myopodin suppressed tumor growth and metastasis [21]. However these observations appear in contradiction with other experiments from Linnemann A. Diplom Thesis 2005 and Krueger Diplom Thesis 2007, where the expression of Myopodin at the protein level could be verify merely in muscle cells.


ReferencesReferences

  1. ↑ 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
  2. ↑ Nelander S, Mostad P, Lindahl P. Prediction of cell type-specific gene modules: identification and initial characterization of a core set of smooth muscle-specific genes. Genome Res. 2003 Aug;13(8):1838-54. Epub 2003 Jul 17. PMID:12869577 doi:10.1101/gr.1197303
  3. ↑ 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
  4. ↑ De Ganck A, De Corte V, Staes A, Gevaert K, Vandekerckhove J, Gettemans J. Multiple isoforms of the tumor suppressor myopodin are simultaneously transcribed in cancer cells. Biochem Biophys Res Commun. 2008 May 30;370(2):269-73. Epub 2008 Mar 25. PMID:18371299 doi:10.1016/j.bbrc.2008.03.086
  5. ↑ Lin F, Yu YP, Woods J, Cieply K, Gooding B, Finkelstein P, Dhir R, Krill D, Becich MJ, Michalopoulos G, Finkelstein S, Luo JH. Myopodin, a synaptopodin homologue, is frequently deleted in invasive prostate cancers. Am J Pathol. 2001 Nov;159(5):1603-12. PMID:11696420 doi:10.1016/S0002-9440(10)63006-4
  6. ↑ Sanchez-Carbayo M, Schwarz K, Charytonowicz E, Cordon-Cardo C, Mundel P. Tumor suppressor role for myopodin in bladder cancer: loss of nuclear expression of myopodin is cell-cycle dependent and predicts clinical outcome. Oncogene. 2003 Aug 14;22(34):5298-305. PMID:12917631 doi:http://dx.doi.org/10.1038/sj.onc.1206616
  7. ↑ Schroeter MM, Beall B, Heid HW, Chalovich JM. In vitro characterization of native mammalian smooth-muscle protein synaptopodin 2. Biosci Rep. 2008 Aug;28(4):195-203. PMID:18588515 doi:10.1042/BSR20080079
  8. ↑ 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
  9. ↑ 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
  10. ↑ Jing L, Liu L, Yu YP, Dhir R, Acquafondada M, Landsittel D, Cieply K, Wells A, Luo JH. Expression of myopodin induces suppression of tumor growth and metastasis. Am J Pathol. 2004 May;164(5):1799-806. PMID:15111326 doi:10.1016/S0002-9440(10)63738-8
  11. ↑ Jing L, Liu L, Yu YP, Dhir R, Acquafondada M, Landsittel D, Cieply K, Wells A, Luo JH. Expression of myopodin induces suppression of tumor growth and metastasis. Am J Pathol. 2004 May;164(5):1799-806. PMID:15111326 doi:10.1016/S0002-9440(10)63738-8
  12. ↑ 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
  13. ↑ Pham M, Chalovich JM. Smooth muscle alpha-actinin binds tightly to fesselin and attenuates its activity toward actin polymerization. J Muscle Res Cell Motil. 2006;27(1):45-51. Epub 2006 Feb 1. PMID:16450054 doi:10.1007/s10974-005-9053-2
  14. ↑ 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
  15. ↑ 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
  16. ↑ 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
  17. ↑ Yu YP, Luo JH. Myopodin-mediated suppression of prostate cancer cell migration involves interaction with zyxin. Cancer Res. 2006 Aug 1;66(15):7414-9. PMID:16885336 doi:10.1158/0008-5472.CAN-06-0227
  18. ↑ Faul C, Dhume A, Schecter AD, Mundel P. Protein kinase A, Ca2+/calmodulin-dependent kinase II, and calcineurin regulate the intracellular trafficking of myopodin between the Z-disc and the nucleus of cardiac myocytes. Mol Cell Biol. 2007 Dec;27(23):8215-27. Epub 2007 Oct 8. PMID:17923693 doi:10.1128/MCB.00950-07
  19. ↑ Lin F, Yu YP, Woods J, Cieply K, Gooding B, Finkelstein P, Dhir R, Krill D, Becich MJ, Michalopoulos G, Finkelstein S, Luo JH. Myopodin, a synaptopodin homologue, is frequently deleted in invasive prostate cancers. Am J Pathol. 2001 Nov;159(5):1603-12. PMID:11696420 doi:10.1016/S0002-9440(10)63006-4
  20. ↑ Sanchez-Carbayo M, Schwarz K, Charytonowicz E, Cordon-Cardo C, Mundel P. Tumor suppressor role for myopodin in bladder cancer: loss of nuclear expression of myopodin is cell-cycle dependent and predicts clinical outcome. Oncogene. 2003 Aug 14;22(34):5298-305. PMID:12917631 doi:http://dx.doi.org/10.1038/sj.onc.1206616
  21. ↑ Jing L, Liu L, Yu YP, Dhir R, Acquafondada M, Landsittel D, Cieply K, Wells A, Luo JH. Expression of myopodin induces suppression of tumor growth and metastasis. Am J Pathol. 2004 May;164(5):1799-806. PMID:15111326 doi:10.1016/S0002-9440(10)63738-8
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