PCNT explained

Pericentrin (kendrin), also known as PCNT and pericentrin-B (PCNTB), is a protein which in humans is encoded by the PCNT gene on chromosome 21.^{[1] [2] [3] [4]} This protein localizes to the centrosome and recruits proteins to the pericentriolar matrix (PCM) to ensure proper centrosome and mitotic spindle formation, and thus, uninterrupted cell cycle progression.^{[5] [6] [7] [8]} This gene is implicated in many diseases and disorders, including congenital disorders such as microcephalic osteodysplastic primordial dwarfism type II (MOPDII) and Seckel syndrome.^{[5] [6]}

Structure

PCNT is a 360 kDa protein which contains a series of coiled coil domains and a highly conserved PCM targeting motif called the PACT domain near its C-terminus.^{[1] [4] [5] [6] [7] [9] [10]} The PACT domain is responsible for targeting the protein to the centrosomes and attaching it to the centriole walls during interphase.^{[5] [6]} In addition, PCNT possesses five nuclear export sequences which all contribute to its nuclear export into the cytoplasm, as well as one nuclear localization signal composed of three clusters of basic amino acids, all of which contribute to the protein's nuclear localization.^[5]

PCNTB, a cDNA homolog of PCNT, was identified and described by Li et al. to share a sequence identity of 61% and similarity of 75%. However, compared to PCNT, PCNTB contains an additional coiled coil domain and unique 1000-residue C-terminus, suggesting that these two may be separate proteins in a new CPM superfamily.^[4] As with PCNT, the C-terminus of PCNTB contains functional domains for centriole localization and CEP215 binding. The N-terminus may also contain a functional domain that associates with the C-terminus domain, and this association is required for engagement with the centriole.^[11]

Function

The protein encoded by this gene is expressed in the cytoplasm and centrosome throughout the cell cycle, and to a lesser extent, in the nucleus. It is an integral component of the PCM, which is a centrosome scaffold that anchors microtubule nucleating complexes and other centrosomal proteins.^{[4] [5] [7] [11] [12]} In one model, PCNT complexes with CEP215 and is phosphorylated by PLK1, leading to PCM component recruitment and organization, centrosome maturation, and spindle formation.^{[6] [11]} The protein controls the nucleation of microtubules by interacting with the microtubule nucleation component γ-tubulin, thus anchoring the γ-tubulin ring complex to the centrosome, which is essential for bipolar spindle formation and chromosome assembly in early mitosis.^{[5] [6] [7] [8]} This ensures normal function and organization of the centrosomes, mitotic spindles, and cytoskeleton, and by extension, regulation over cell cycle progression and checkpoints.^{[5] [6] [7] [12]} Downregulation of PCNT disrupted mitotic checkpoints and arrested the cell at the G2/M checkpoint, leading to cell death.^{[10] [12]} Moreover, microtubule functioning was also disrupted, resulting in mono- or multipolar spindles, chromosomal misalignment, premature sister chromatid separation, and aneuploidy.^{[6] [12]}

PCNT is highly abundant in skeletal muscle, indicating that it may be involved in muscle insulin action.^[7] PCNT is also involved in neuronal development through its interaction with DISC1 to regulate microtubule organization.^[8]

Clinical significance

Mutations in the PCNT gene have been linked to Down syndrome (DS); two types of primordial dwarfism, MOPDII and Seckel syndrome; intrauterine growth retardation; cardiomyopathy; early onset type 2 diabetes; chronic myeloid leukemia (CML); bipolar affective disorder; and other congenital disorders.^{[5] [6] [8] [10] [11] [12]} In particular, the short stature and small brain size characteristic of MOPDII and Seckel syndrome have been attributed to centrosome dysfunction and cell growth disruption as a result of PCNT malfunction.^[5] Additionally, premature aging, cerebral involution, inflammatory and immune responses are linked to DS associated with PCNT mutations, while severe insulin resistance, diabetes, and dyslipidemia are featured in MOPDII associated with PCNT mutations.^{[7] [10]}

Interactions

PCNT has been shown to interact with:

• calmodulin,
• separase,^[11]
• CEP215,^[6]
• CHD3/4,^[5]
• protein kinase A,^[5]
• protein kinase C,^[5]
• DISC1,^[5]
• γ-tubulin complex proteins,^[5] and
• PCM1.^{[4] [5]}

Further reading

• Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T . Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones . DNA Research . 9 . 3 . 99–106 . Jun 2002 . 12168954 . 10.1093/dnares/9.3.99 . free .
• Chen H, Gos A, Morris MA, Antonarakis SE . Localization of a human homolog of the mouse pericentrin gene (PCNT) to chromosome 21qter . Genomics . 35 . 3 . 620–4 . Aug 1996 . 8812505 . 10.1006/geno.1996.0411 .
• Ishikawa K, Nagase T, Nakajima D, Seki N, Ohira M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . Prediction of the coding sequences of unidentified human genes. VIII. 78 new cDNA clones from brain which code for large proteins in vitro . DNA Research . 4 . 5 . 307–13 . Oct 1997 . 9455477 . 10.1093/dnares/4.5.307 . free .
• Diviani D, Langeberg LK, Doxsey SJ, Scott JD . Pericentrin anchors protein kinase A at the centrosome through a newly identified RII-binding domain . Current Biology . 10 . 7 . 417–20 . Apr 2000 . 10753751 . 10.1016/S0960-9822(00)00422-X . 2535595 . free . 2000CBio...10..417D .
• Flory MR, Moser MJ, Monnat RJ, Davis TN . Identification of a human centrosomal calmodulin-binding protein that shares homology with pericentrin . Proceedings of the National Academy of Sciences of the United States of America . 97 . 11 . 5919–23 . May 2000 . 10823944 . 18534 . 10.1073/pnas.97.11.5919 . 2000PNAS...97.5919F . free .
• Hattori M, Fujiyama A, Taylor TD, Watanabe H, Yada T, Park HS, Toyoda A, Ishii K, Totoki Y, Choi DK, Groner Y, Soeda E, Ohki M, Takagi T, Sakaki Y, Taudien S, Blechschmidt K, Polley A, Menzel U, Delabar J, Kumpf K, Lehmann R, Patterson D, Reichwald K, Rump A, Schillhabel M, Schudy A, Zimmermann W, Rosenthal A, Kudoh J, Schibuya K, Kawasaki K, Asakawa S, Shintani A, Sasaki T, Nagamine K, Mitsuyama S, Antonarakis SE, Minoshima S, Shimizu N, Nordsiek G, Hornischer K, Brant P, Scharfe M, Schon O, Desario A, Reichelt J, Kauer G, Blocker H, Ramser J, Beck A, Klages S, Hennig S, Riesselmann L, Dagand E, Haaf T, Wehrmeyer S, Borzym K, Gardiner K, Nizetic D, Francis F, Lehrach H, Reinhardt R, Yaspo ML . The DNA sequence of human chromosome 21 . Nature . 405 . 6784 . 311–9 . May 2000 . 10830953 . 10.1038/35012518 . 2000Natur.405..311H . free .
• Li Q, Hansen D, Killilea A, Joshi HC, Palazzo RE, Balczon R . Kendrin/pericentrin-B, a centrosome protein with homology to pericentrin that complexes with PCM-1 . Journal of Cell Science . 114 . Pt 4 . 797–809 . Feb 2001 . 10.1242/jcs.114.4.797 . 11171385 .
• Takahashi M, Yamagiwa A, Nishimura T, Mukai H, Ono Y . Centrosomal proteins CG-NAP and kendrin provide microtubule nucleation sites by anchoring gamma-tubulin ring complex . Molecular Biology of the Cell . 13 . 9 . 3235–45 . Sep 2002 . 12221128 . 124155 . 10.1091/mbc.E02-02-0112 .
• Flory MR, Davis TN . The centrosomal proteins pericentrin and kendrin are encoded by alternatively spliced products of one gene . Genomics . 82 . 3 . 401–5 . Sep 2003 . 12906865 . 10.1016/S0888-7543(03)00119-8 .
• Chang F, Re F, Sebastian S, Sazer S, Luban J . HIV-1 Vpr induces defects in mitosis, cytokinesis, nuclear structure, and centrosomes . Molecular Biology of the Cell . 15 . 4 . 1793–801 . Apr 2004 . 14767062 . 379276 . 10.1091/mbc.E03-09-0691 .
• Miyoshi K, Asanuma M, Miyazaki I, Diaz-Corrales FJ, Katayama T, Tohyama M, Ogawa N . DISC1 localizes to the centrosome by binding to kendrin . Biochemical and Biophysical Research Communications . 317 . 4 . 1195–9 . May 2004 . 15094396 . 10.1016/j.bbrc.2004.03.163 .
• Jurczyk A, Gromley A, Redick S, San Agustin J, Witman G, Pazour GJ, Peters DJ, Doxsey S . Pericentrin forms a complex with intraflagellar transport proteins and polycystin-2 and is required for primary cilia assembly . The Journal of Cell Biology . 166 . 5 . 637–43 . Aug 2004 . 15337773 . 2172416 . 10.1083/jcb.200405023 .
• Suzuki Y, Yamashita R, Shirota M, Sakakibara Y, Chiba J, Mizushima-Sugano J, Nakai K, Sugano S . Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions . Genome Research . 14 . 9 . 1711–8 . Sep 2004 . 15342556 . 515316 . 10.1101/gr.2435604 .
• Golubkov VS, Chekanov AV, Doxsey SJ, Strongin AY . Centrosomal pericentrin is a direct cleavage target of membrane type-1 matrix metalloproteinase in humans but not in mice: potential implications for tumorigenesis . The Journal of Biological Chemistry . 280 . 51 . 42237–41 . Dec 2005 . 16251193 . 10.1074/jbc.M510139200 . free .
• Nousiainen M, Silljé HH, Sauer G, Nigg EA, Körner R . Phosphoproteome analysis of the human mitotic spindle . Proceedings of the National Academy of Sciences of the United States of America . 103 . 14 . 5391–6 . Apr 2006 . 16565220 . 1459365 . 10.1073/pnas.0507066103 . 2006PNAS..103.5391N . free .

Notes and References

1. Web site: Entrez Gene: PCNT pericentrin (kendrin).
2. Chen H, Gos A, Morris MA, Antonarakis SE . Localization of a human homolog of the mouse pericentrin gene (PCNT) to chromosome 21qter . Genomics . 35 . 3 . 620–4 . Aug 1996 . 8812505 . 10.1006/geno.1996.0411 .
3. Flory MR, Moser MJ, Monnat RJ, Davis TN . Identification of a human centrosomal calmodulin-binding protein that shares homology with pericentrin . Proceedings of the National Academy of Sciences of the United States of America . 97 . 11 . 5919–23 . May 2000 . 10823944 . 18534 . 10.1073/pnas.97.11.5919 . 2000PNAS...97.5919F . free .
4. Li Q, Hansen D, Killilea A, Joshi HC, Palazzo RE, Balczon R . Kendrin/pericentrin-B, a centrosome protein with homology to pericentrin that complexes with PCM-1 . Journal of Cell Science . 114 . Pt 4 . 797–809 . Feb 2001 . 10.1242/jcs.114.4.797 . 11171385 .
5. Liu Q, Yu J, Zhuo X, Jiang Q, Zhang C . Pericentrin contains five NESs and an NLS essential for its nucleocytoplasmic trafficking during the cell cycle . Cell Research . 20 . 8 . 948–62 . Aug 2010 . 20567258 . 10.1038/cr.2010.89 . free .
6. Kim S, Rhee K . Importance of the CEP215-pericentrin interaction for centrosome maturation during mitosis . PLOS ONE . 9 . 1 . e87016 . 2014 . 24466316 . 10.1371/journal.pone.0087016 . 3899370. 2014PLoSO...987016K . free .
7. Huang-Doran I, Bicknell LS, Finucane FM, Rocha N, Porter KM, Tung YC, Szekeres F, Krook A, Nolan JJ, O'Driscoll M, Bober M, O'Rahilly S, Jackson AP, Semple RK . Genetic defects in human pericentrin are associated with severe insulin resistance and diabetes . Diabetes . 60 . 3 . 925–35 . Mar 2011 . 21270239 . 10.2337/db10-1334 . 3046854.
8. Shimizu S, Matsuzaki S, Hattori T, Kumamoto N, Miyoshi K, Katayama T, Tohyama M . DISC1-kendrin interaction is involved in centrosomal microtubule network formation . Biochemical and Biophysical Research Communications . 377 . 4 . 1051–6 . Dec 2008 . 18955030 . 10.1016/j.bbrc.2008.10.100 .
9. Gillingham AK, Munro S . The PACT domain, a conserved centrosomal targeting motif in the coiled-coil proteins AKAP450 and pericentrin . EMBO Reports . 1 . 6 . 524–9 . Dec 2000 . 11263498 . 1083777 . 10.1093/embo-reports/kvd105 .
10. Salemi M, Barone C, Romano C, Salluzzo R, Caraci F, Cantarella RA, Salluzzo MG, Drago F, Romano C, Bosco P . Pericentrin expression in Down's syndrome . Neurological Sciences . 34 . 11 . 2023–5 . Nov 2013 . 23979692 . 10.1007/s10072-013-1529-z . 1823570 .
11. Lee K, Rhee K . Separase-dependent cleavage of pericentrin B is necessary and sufficient for centriole disengagement during mitosis . Cell Cycle . 11 . 13 . 2476–85 . Jul 2012 . 22722493 . 10.4161/cc.20878 . free .
12. Unal S, Alanay Y, Cetin M, Boduroglu K, Utine E, Cormier-Daire V, Huber C, Ozsurekci Y, Kilic E, Simsek Kiper OP, Gumruk F . Striking hematological abnormalities in patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD II): a potential role of pericentrin in hematopoiesis . Pediatric Blood & Cancer . 61 . 2 . 302–5 . Feb 2014 . 24106199 . 10.1002/pbc.24783 . 13192693 .