Jump to content

Draft:Par Proteins

From Wikipedia, the free encyclopedia

Par (Partitioning defective) proteins are a highly conserved network essential for establishing and maintaining cell polarity. They function across diverse polarity contexts, including asymmetric cell division, apical-basal polarity in epithelial cells, neuronal development, and oriented cell migration. Initially identified in C. elegans, mutations in Par genes cause defects in asymmetric daughter cell formation.[1] The six Par proteins—Par1, Par2, Par3, Par4, Par5, and Par6—are largely conserved across species, except Par2, which is unique to C. elegans. Each protein contributes distinct but interconnected roles in maintaining polarity, with the Par3/Par6/aPKC complex playing a central role in organizing cellular domains.

The distribution of anterior (green) and posterior (red) par proteins during the first two divisions of embryonic blastomeres. Originally published in[2]

History

[edit]

In 1988, Par genes were first identified in C. elegans through a genetic screening of embryogenesis.[1] Loss-of-function mutations led to defective asymmetrical division in the C. elegans zygote (one-cell-stage embryo), leading to the genes being named “Par” genes, short for “partitioning”. Through this screen, six Par genes were identified to be required for interpreting the polarity signals provided by the sperm to establish the polarity axis required for the asymmetric division that leads to embryonic anterior-posterior polarity.[1][3] Later work in C. elegans expanded the role of Par proteins to various polarization processes of many different cell types, including those involved in gastrulation, epithelial cells, and migrating cells.[4][5][6]

Until 1998, little was known about Par proteins outside of C. elegans. In 1998, the Drosophila polarity gene, bazooka (Baz), was identified as homologous to Par3,[7] marking the beginning of research into Par proteins across other species.

Roles of individual Par proteins

[edit]

Each Par protein contributes distinct yet interconnected functions to establish and maintain cellular polarity.

Par1

[edit]

Par1 is a serine/threonine protein kinase that localizes to the posterior domain of polarized cells with Par2.[8] Par1 is also involved in microtubule organization.[9][10] C. elegans and Drosophila encode a single Par1 protein that is essential for embryonic development. In the Drosophila oocyte, alternatively spliced isoforms have distinct localization patterns and functional roles. [11]

Par2

[edit]

Par2 is a scaffold protein with a RING finger domain.[12] In the C. elegans zygote, Par2 plays a crucial role in defining the posterior domain by recruiting and stabilizing Par1 at the cortical region. Unlike other Par proteins, Par2 is unique to C. elegans, with no evidence of its presence in Drosophila or mammals.

Par3

[edit]

Par3 is a large scaffold protein containing three PDZ domains that enable interactions with multiple partners, including Par6, aPKC, and tight junction components. It is a central organizer of the anterior complex, recruiting other proteins to apical or anterior regions and coordinating the assembly of cell-cell junctions. Par3 has been reported to have many distinct interactions with various molecules.[13][14][15][16][17][18][19] C. elegans and Drosophila each have one Par3 protein, with the Drosophila homolog called Baz, short for “Bazooka”. Two Par3 homologs exist in mammals (Pard3 and Pard3β in mice, and PARD3 and PARD3β, or PARD3B in humans).

Par4

[edit]

Par4, also known as LKB1 in mammals, is a serine/threonine protein kinase.[20] In C. elegans Par4 was identified to be important for cytoplasmic localization and intestinal cell development during embryogenesis.[20] In mammals, LKB1 is proposed to be a regulator of intestinal homeostasis.[21][22]

Par5

[edit]

Par5, also known as 14-3-3 proteins in mammals, functions as a regulatory scaffold that binds to phosphorylated Par proteins. The distribution of Par5 throughout the cytoplasm aids in its role of maintaining polarity between the Par3/Par6/aPKC complex and Par2 proteins.[23]

Par6

[edit]

Par6 is an adaptor scaffolding protein with a PDZ domain and a CRIB domain for binding to Cdc42, a small GTPase. C. elegans and Drosophila each have one Par6 protein, with the Drosophila homolog called DmPar-6. Two Par6 homologs exist in mammals (Pard6α, Pard6β, and Pard6γ in mice and PARD6α, PARD6β, and PARD6γ in humans).

Par3/Par6/aPKC complex

[edit]

The Par6/Par3/aPKC complex, or simply the Par complex, is a tripartite assembly composed of three main proteins: Par6, Par3, and atypical protein kinase C (aPKC). Each component contributes distinct yet complementary functionalities, enabling the complex to serve as a versatile regulator of cellular processes.

  • aPKC, atypical protein kinase c, is the catalytic component of the complex. As a kinase, it phosphorylates various substrates to execute its polarity-related functions. Unlike conventional PKCs, aPKC does not require calcium or diacylglycerol for its activity and instead relies on upstream signals from PAR6 and other regulators. aPKC tightly binds with PAR6, forming a heterodimer24–26.[24][25][26] In 2020, it was found that aPKC binds to PAR3 via a PDZ-binding motif at aPKC’s C-terminus.[13]
  • Par6 is a scaffolding protein characterized by its PDZ domain and CRIB (Cdc42/Rac interactive binding) domain.
  • Par3 is a scaffold protein with three conserved PDZ domains[7] and modulates the activity of aPKC.

The PAR complex, functions to create distinct, polarized domains of the cell cortex. Through actomyosin-generated cortical flow, the PAR complex becomes polarized to one cortical domain and keeps other, cell type-specific factors, localized to an opposite cortical domain.[27][28][29][30][31]

Historically, mentions of the Par complex referred to the assembly Par3, Par6, and aPKC, but recent studies have proposed that there are two complexes formed by the Par6/aPKC heterodimer: one that binds Par3 and another that binds the Rho GTPase Cdc42. When Par3 is bound to Par6/aPKC, the complex is inactive and aPKC activity is inhibited. The transition to Cdc42 bound state maintains the Par complex at the cell cortex while stimulating aPKC activity32–34. [32][33][34]

Asymmetric cell division

[edit]

In asymmetric cell division, Par proteins establish polarity axes that dictate the unequal distribution of cell fate determinants. After fertilization of the C. elegans zygote, Par3, Par6, and aPKC are uniformly distributed throughout the cortex, while Par1 and Par2 are in the cytoplasm. Cortical flow away from the posterior pole initiates the formation of the anterior-posterior axis through segregation of Par proteins. The Par3/Par6/aPKC complex and Cdc24 are known as the anterior Par proteins, localizing to the anterior domain of the embryo cortex. Par2 and Par 1 are the posterior Par proteins, localizing to the posterior domain of the embryo cortex. After Par2 localizes to the posterior cortex, it recruits Par1 to exclude the anterior Par proteins via Par1-dependent phosphorylation of Par3.[35] Mutual antagonism of the anterior and posterior Par proteins maintains this polarity. This segregation guides the orientation of the mitotic spindle and asymmetric inheritance of cell fate determinants.

Apical-basal polarity of epithelial cells

[edit]

Epithelial cells exhibit apical-basal polarity, with distinct apical and basolateral domains that are critical for their barrier and absorptive functions. aPKC is recruited to the apical cortex, where it excludes basolateral proteins, whereas Par1 is recruited to the basolateral cortex and excludes apical proteins.

Epithelial cells form apical intercellular junctions with neighboring cells. In the developing Drosophila embryo, Par3 localizes to the apical-lateral junctions between epithelial cells and recruits cadherin clusters which grow into adherens junctions.[36]

Par complex localizes to the tight junctions on the apical side of the epithelial cell. Par1 is localized to the basolateral membrane. Originally published in[37]

Cell migration

[edit]

Par proteins are essential for cell migration. Migrating cells establish a leading process and a trailing edge, with the Par3/Par6/aPKC complex localized to the leading edge. This complex regulates cytoskeletal dynamics and adhesion, enabling migrating cells to move toward their target destinations.

Neuronal development

[edit]

Neurons are highly polarized cells with two functionally and structurally distinct compartments, axons and dendrites, within one cell. The Par3/Par6/aPKC complex accumulates at the tips of axons, and mediates signaling from Cdc42 to Rac1, which influences the dynamics of actin filaments at the tip of the axon to enhance rapid axon outgrowth and specification.[38][39] Par proteins are also key to synapse formation and plasticity. By localizing to synaptic regions, the Par3/Par6/aPKC complex regulate the formation, maintenance, and remodeling of synapses. Additionally, the localized synthesis of Par proteins at synapses also underpins synaptic long-term potentiation, an essential process for memory and learning.[39]

Cancer

[edit]

Proper polarity regulated by Par proteins, is essential for tissue homeostasis, cellular differentiation, and migration. Loss of polarity is a hallmark of cancer, with Par protein dysregulation linked to tumor progression. For instance, Par6-mediated degradation of RhoA promotes epithelial-to-mesenchymal transition (EMT), enabling increased motility and invasion. For instance, overactivation of aPKC is also associated with epithelial-to-mesenchymal transition (EMT). Deregulation of aPKC activity has also been suggested to promote tumor growth. Additionally, aPKC isoforms have been implicated in various human malignancies.[40][41][42]

Neurodevelopmental disorders

[edit]

Par complexes regulate the spatial organization of neurons, which is crucial for normal brain architecture and function. Dysregulation in cell polarity affects neurodevelopment and contributes to disorders such as schizophrenia and bipolar disorder. In schizophrenia, Par complex dysfunction disrupts synaptic adhesion and connectivity, contributing to abnormal brain networks. Genetic studies have linked mutations in PARD3 and aPKC pathways to schizophrenia-like phenotypes, suggesting these proteins are necessary for maintaining synaptic integrity and neural circuitry.[43][44] Furthermore, interactions between Par complexes and pathways such as GSK3β signaling may underlie mood instability in bipolar disorder. Two genetic studies, one in the Bulgarian population and the other in South African Xhosa population implicated PARD6β in bipolar disorder.[45][46]

See also

[edit]

References

[edit]
  1. ^ a b c Kemphues, K.J., Priess, J.R., Morton, D.G., and Cheng, N. (1988). Identification of genes required for cytoplasmic localization in early C. elegans embryos. Cell 52, 311–320. https://doi.org/10.1016/S0092-8674(88)80024-2.
  2. ^ Rabilotta A, Desrosiers M, Labbé JC (2015) PLOS One https://doi.org/10.1371/journal.pone.0117656
  3. ^ Kemphues, K. (2000). PARsing Embryonic Polarity. Cell 101, 345–348. https://doi.org/10.1016/S0092-8674(00)80844-2.
  4. ^ Nance, J. (2005). PAR proteins and the establishment of cell polarity during C. elegans development. BioEssays 27, 126–135. https://doi.org/10.1002/bies.20175.
  5. ^ Aono, S., Legouis, R., Hoose, W.A., and Kemphues, K.J. (2004). PAR-3 is required for epithelial cell polarity in the distal spermatheca of C. elegans. Development 131, 2865–2874. https://doi.org/10.1242/dev.01146.
  6. ^ Welchman, D.P., Mathies, L., and Ahringer, J. (2007). Similar requirements for CDC-42 and the PAR-3/PAR-6/PKC-3 complex in diverse cell types. Dev Biol 305, 347–357. https://doi.org/10.1016/j.ydbio.2007.02.022.
  7. ^ a b Kurzchalia, T., and Hartmann, E. (1996). Are there similarities between the polarization of the C. elegans embryo and of an epithelial cell? Trends in Cell Biology 6, 131–132. https://doi.org/10.1016/0962-8924(96)20003-0.
  8. ^ Guo, S., and Kemphues, K.J. (1995). par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed. Cell 81, 611–620. https://doi.org/10.1016/0092-8674(95)90082-9.
  9. ^ Doerflinger, H., Vogt, N., Torres, I.L., Mirouse, V., Koch, I., Nüsslein-Volhard, C., and St Johnston, D. (2010). Bazooka is required for polarisation of the Drosophila anterior-posterior axis. Development 137, 1765–1773. https://doi.org/10.1242/dev.045807.
  10. ^ Parton, R.M., Hamilton, R.S., Ball, G., Yang, L., Cullen, C.F., Lu, W., Ohkura, H., and Davis, I. (2011). A PAR-1–dependent orientation gradient of dynamic microtubules directs posterior cargo transport in the Drosophila oocyte. Journal of Cell Biology 194, 121–135. https://doi.org/10.1083/jcb.201103160.
  11. ^ Doerflinger, H., Benton, R., Torres, I.L., Zwart, M.F., and St Johnston, D. (2006). Drosophila Anterior-Posterior Polarity Requires Actin-Dependent PAR-1 Recruitment to the Oocyte Posterior. Current Biology 16, 1090–1095. https://doi.org/10.1016/j.cub.2006.04.001.
  12. ^ Levitan, D.J., Boyd, L., Mello, C.C., Kemphues, K.J., and Stinchcomb, D.T. (1994). par-2, a gene required for blastomere asymmetry in Caenorhabditis elegans, encodes zinc-finger and ATP-binding motifs. Proc Natl Acad Sci U S A 91, 6108–6112.
  13. ^ a b Holly, R.W., Jones, K., and Prehoda, K.E. (2020). A Conserved PDZ-Binding Motif in aPKC Interacts with Par-3 and Mediates Cortical Polarity. Current Biology 30, 893-898.e5. https://doi.org/10.1016/j.cub.2019.12.055.
  14. ^ Joberty, G., Petersen, C., Gao, L., and Macara, I.G. (2000). The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42. Nat Cell Biol 2, 531–539. https://doi.org/10.1038/35019573.
  15. ^ Lin, D., Edwards, A.S., Fawcett, J.P., Mbamalu, G., Scott, J.D., and Pawson, T. (2000). A mammalian PAR-3-PAR-6 complex implicated in Cdc42/Rac1 and aPKC signalling and cell polarity. Nat Cell Biol 2, 540–547. https://doi.org/10.1038/35019582.
  16. ^ Qiu, R.G., Abo, A., and Steven Martin, G. (2000). A human homolog of the C. elegans polarity determinant Par-6 links Rac and Cdc42 to PKCzeta signaling and cell transformation. Curr Biol 10, 697–707. https://doi.org/10.1016/s0960-9822(00)00535-2.
  17. ^ Garrard, S.M., Capaldo, C.T., Gao, L., Rosen, M.K., Macara, I.G., and Tomchick, D.R. (2003). Structure of Cdc42 in a complex with the GTPase-binding domain of the cell polarity protein, Par6. EMBO J 22, 1125–1133. https://doi.org/10.1093/emboj/cdg110.
  18. ^ Izumi, Y., Hirose, T., Tamai, Y., Hirai, S., Nagashima, Y., Fujimoto, T., Tabuse, Y., Kemphues, K.J., and Ohno, S. (1998). An atypical PKC directly associates and colocalizes at the epithelial tight junction with ASIP, a mammalian homologue of Caenorhabditis elegans polarity protein PAR-3. J Cell Biol 143, 95–106. https://doi.org/10.1083/jcb.143.1.95.
  19. ^ Li, J., Kim, H., Aceto, D.G., Hung, J., Aono, S., and Kemphues, K.J. (2010). Binding to pkc-3, but not to par-3 or to a conventional pdz domain ligand, is required for par-6 function in C. elegans. Dev Biol 340, 88–98. https://doi.org/10.1016/j.ydbio.2010.01.023.
  20. ^ a b Morton, D.G., Roos, J.M., and Kemphues, K.J. (1992). par-4, a gene required for cytoplasmic localization and determination of specific cell types in Caenorhabditis elegans embryogenesis. Genetics 130, 771–790. https://doi.org/10.1093/genetics/130.4.771.
  21. ^ Baas, A.F., Kuipers, J., Wel, N.N. van der, Batlle, E., Koerten, H.K., Peters, P.J., and Clevers, H.C. (2004). Complete Polarization of Single Intestinal Epithelial Cells upon Activation of LKB1 by STRAD. Cell 116, 457–466. https://doi.org/10.1016/S0092-8674(04)00114-X.
  22. ^ Shorning, B.Y., Zabkiewicz, J., McCarthy, A., Pearson, H.B., Winton, D.J., Sansom, O.J., Ashworth, A., and Clarke, A.R. (2009). Lkb1 Deficiency Alters Goblet and Paneth Cell Differentiation in the Small Intestine. PLOS ONE 4, e4264. https://doi.org/10.1371/journal.pone.0004264.
  23. ^ Morton, D.G., Shakes, D.C., Nugent, S., Dichoso, D., Wang, W., Golden, A., and Kemphues, K.J. (2002). The Caenorhabditis elegans par-5 Gene Encodes a 14-3-3 Protein Required for Cellular Asymmetry in the Early Embryo. Developmental Biology 241, 47–58. https://doi.org/10.1006/dbio.2001.0489.
  24. ^ Suzuki, A., Yamanaka, T., Hirose, T., Manabe, N., Mizuno, K., Shimizu, M., Akimoto, K., Izumi, Y., Ohnishi, T., and Ohno, S. (2001). Atypical protein kinase C is involved in the evolutionarily conserved par protein complex and plays a critical role in establishing epithelia-specific junctional structures. J Cell Biol 152, 1183–1196. https://doi.org/10.1083/jcb.152.6.1183.
  25. ^ Yamanaka, T., Horikoshi, Y., Suzuki, A., Sugiyama, Y., Kitamura, K., Maniwa, R., Nagai, Y., Yamashita, A., Hirose, T., Ishikawa, H., et al. (2001). PAR-6 regulates aPKC activity in a novel way and mediates cell-cell contact-induced formation of the epithelial junctional complex. Genes Cells 6, 721–731. https://doi.org/10.1046/j.1365-2443.2001.00453.x.
  26. ^ Sarıkaya, S., and Dickinson, D.J. (2021). Rapid extraction and kinetic analysis of protein complexes from single cells. Biophys J 120, 5018–5031. https://doi.org/10.1016/j.bpj.2021.10.011.
  27. ^ Prehoda, K.E. (2009). Polarization of Drosophila Neuroblasts During Asymmetric Division. Cold Spring Harb Perspect Biol 1, a001388. https://doi.org/10.1101/cshperspect.a001388.
  28. ^ Knoblich, J.A. (2010). Asymmetric cell division: recent developments and their implications for tumour biology. Nat Rev Mol Cell Biol 11, 849–860. https://doi.org/10.1038/nrm3010.
  29. ^ Munro, E., Nance, J., and Priess, J.R. (2004). Cortical Flows Powered by Asymmetrical Contraction Transport PAR Proteins to Establish and Maintain Anterior-Posterior Polarity in the Early C. elegans Embryo. Developmental Cell 7, 413–424. https://doi.org/10.1016/j.devcel.2004.08.001.
  30. ^ Hutterer, A., Betschinger, J., Petronczki, M., and Knoblich, J.A. (2004). Sequential Roles of Cdc42, Par-6, aPKC, and Lgl in the Establishment of Epithelial Polarity during Drosophila Embryogenesis. Developmental Cell 6, 845–854. https://doi.org/10.1016/j.devcel.2004.05.003.
  31. ^ Oon, C.H., and Prehoda, K.E. Asymmetric recruitment and actin-dependent cortical flows drive the neuroblast polarity cycle. eLife 8, e45815. https://doi.org/10.7554/eLife.45815.
  32. ^ Rodriguez, J., Peglion, F., Martin, J., Hubatsch, L., Reich, J., Hirani, N., Gubieda, A.G., Roffey, J., Fernandes, A.R., St Johnston, D., et al. (2017). aPKC Cycles between Functionally Distinct PAR Protein Assemblies to Drive Cell Polarity. Dev Cell 42, 400-415.e9. https://doi.org/10.1016/j.devcel.2017.07.007.
  33. ^ Wang, S.-C., Low, T.Y.F., Nishimura, Y., Gole, L., Yu, W., and Motegi, F. (2017). Cortical forces and CDC-42 control clustering of PAR proteins for Caenorhabditis elegans embryonic polarization. Nat Cell Biol 19, 988–995. https://doi.org/10.1038/ncb3577.
  34. ^ Dickinson, D.J., Schwager, F., Pintard, L., Gotta, M., and Goldstein, B. (2017). A Single-Cell Biochemistry Approach Reveals PAR Complex Dynamics during Cell Polarization. Developmental Cell 42, 416-434.e11. https://doi.org/10.1016/j.devcel.2017.07.024.
  35. ^ Motegi, F., Zonies, S., Hao, Y., Cuenca, A.A., Griffin, E., and Seydoux, G. (2011). Microtubules induce self-organization of polarized PAR domains in Caenorhabditis elegans zygotes. Nat Cell Biol 13, 1361–1367. https://doi.org/10.1038/ncb2354.
  36. ^ McGill, M.A., McKinley, R.F.A., and Harris, T.J.C. (2009). Independent cadherin-catenin and Bazooka clusters interact to assemble adherens junctions. J Cell Biol 185, 787–796. https://doi.org/10.1083/jcb.200812146.
  37. ^ Zhang, Huaye, Polarity Determinants in Dendritic Spine Development and Plasticity, Neural Plasticity, 2016, 3145019, 10 pages, 2016. https://doi.org/10.1155/2016/3145019
  38. ^ Arimura, N., and Kaibuchi, K. (2007). Neuronal polarity: from extracellular signals to intracellular mechanisms. Nat Rev Neurosci 8, 194–205. https://doi.org/10.1038/nrn2056.
  39. ^ a b Sacktor, T.C. (2011). How does PKMζ maintain long-term memory? Nat Rev Neurosci 12, 9–15. https://doi.org/10.1038/nrn2949.
  40. ^ Fields, A.P., and Regala, R.P. (2007). Protein kinase Cι: human oncogene, prognostic marker and therapeutic target. Pharmacol Res 55, 487–497. https://doi.org/10.1016/j.phrs.2007.04.015.
  41. ^ Eder, A.M., Sui, X., Rosen, D.G., Nolden, L.K., Cheng, K.W., Lahad, J.P., Kango-Singh, M., Lu, K.H., Warneke, C.L., Atkinson, E.N., et al. (2005). Atypical PKCι contributes to poor prognosis through loss of apical-basal polarity and Cyclin E overexpression in ovarian cancer. Proc Natl Acad Sci U S A 102, 12519–12524. https://doi.org/10.1073/pnas.0505641102.
  42. ^ Regala, R.P., Weems, C., Jamieson, L., Khoor, A., Edell, E.S., Lohse, C.M., and Fields, A.P. (2005). Atypical protein kinase C iota is an oncogene in human non-small cell lung cancer. Cancer Res 65, 8905–8911. https://doi.org/10.1158/0008-5472.CAN-05-2372.
  43. ^ Kim, S.K., Lee, J.Y., Park, H.J., Kim, J.W., and Chung, J.-H. (2012). Association study between polymorphisms of the PARD3 gene and schizophrenia. Exp Ther Med 3, 881–885.
  44. ^ Kushima, I., Aleksic, B., Nakatochi, M., Shimamura, T., Okada, T., Uno, Y., Morikawa, M., Ishizuka, K., Shiino, T., Kimura, H., et al. (2018). Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights. Cell Rep 24, 2838–2856. https://doi.org/10.1016/j.celrep.2018.08.022.https://doi.org/10.3892/etm.2012.496.
  45. ^ Yosifova, A., Mushiroda, T., Kubo, M., Takahashi, A., Kamatani, Y., Kamatani, N., Stoianov, D., Vazharova, R., Karachanak, S., Zaharieva, I., et al. (2011). Genome-wide association study on bipolar disorder in the Bulgarian population. Genes Brain Behav 10, 789–797. https://doi.org/10.1111/j.1601-183X.2011.00721.x.
  46. ^ Gulsuner, S., Stein, D.J., Susser, E.S., Sibeko, G., Pretorius, A., Walsh, T., Majara, L., Mndini, M.M., Mqulwana, S.G., Ntola, O.A., et al. (2020). Genetics of schizophrenia in the South African Xhosa. Science 367, 569–573. https://doi.org/10.1126/science.aay8833.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Draft:Par_Proteins&oldid=1262538798"