Affinage

TPPP2

Tubulin polymerization-promoting protein family member 2 · UniProt P59282

Length
170 aa
Mass
18.5 kDa
Annotated
2026-04-28
100 papers in source corpus 1 papers cited in narrative 1 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TPPP2 localizes to elongating spermatids and mature sperm, where it is essential for mitochondrial cristae integrity, electron transport chain function, and ATP production (PMID:30680919). Knockout of TPPP2 in mice causes oligoasthenozoospermia and male subfertility, with sperm displaying abnormal mitochondria lacking lamellar cristae, reduced mitochondrial membrane potential, and decreased motility (PMID:30680919). TPPP2 physically interacts with eEF1b (eukaryotic translation elongation factor 1 beta), though the functional significance of this interaction is not yet defined (PMID:30680919).

Mechanistic history

Synthesis pass · year-by-year structured walk · 1 step
  1. 2019 High

    The first functional characterization of TPPP2 established that it is a spermatid/sperm-expressed protein required for mitochondrial cristae formation, oxidative phosphorylation, and male fertility, resolving the previously unknown role of this tubulin polymerization promoting protein family member.

    Evidence TPPP2 knockout mouse with ultrastructural EM, mitochondrial membrane potential and ATP assays, in vitro inhibition, and pulldown identifying eEF1b as interactor

    PMID:30680919

    Open questions at the time
    • Mechanism by which TPPP2 maintains mitochondrial cristae structure is unknown
    • Functional significance of the TPPP2–eEF1b interaction has not been determined
    • Whether TPPP2 acts on tubulin polymerization in spermatids, as implied by its family membership, has not been tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular mechanism linking TPPP2 to mitochondrial cristae organization — whether direct or indirect — remains unresolved, and it is unknown whether TPPP2 has tubulin polymerization-promoting activity in germ cells.
  • No structural or biochemical reconstitution of TPPP2 activity
  • No independent replication of the knockout phenotype by another laboratory
  • Role of TPPP2 in human male infertility has not been investigated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Localization
GO:0005739 mitochondrion 1
Pathway
R-HSA-1474165 Reproduction 1
Partners
EEF1B2

Evidence

Reading pass · 1 per-paper finding extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 TPPP2 protein localizes to elongating spermatids and mature sperm; in vitro inhibition of TPPP2 causes decreased sperm motility and ATP content; knockout mice show male subfertility with decreased sperm count and motility, associated with abnormal mitochondria lacking lamellar cristae, defective electron transfer chain, lower ATP levels, and decreased mitochondrial membrane potential in sperm. A potential TPPP2-interacting protein, eEF1b (eukaryotic translation elongation factor 1 beta), was identified by pulldown. Knockout mouse model, in vitro inhibition assay, co-immunoprecipitation/pulldown for interacting partner identification, subcellular localization by imaging, mitochondrial function assays (ATP measurement, membrane potential, electron microscopy) Journal of cellular and molecular medicine High 30680919

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function. Genes & development 765 8001816
1995 Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. Molecular and cellular biology 618 7739547
1998 Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia-lymphoma cells. Leukemia 350 9639410
1998 CDK inhibitors p18(INK4c) and p27(Kip1) mediate two separate pathways to collaboratively suppress pituitary tumorigenesis. Genes & development 330 9744866
2012 Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18. The Journal of biological chemistry 304 22685290
1995 Mutations in the p16INK4/MTS1/CDKN2, p15INK4B/MTS2, and p18 genes in primary and metastatic lung cancer. Cancer research 271 7882351
2009 The novel lipid raft adaptor p18 controls endosome dynamics by anchoring the MEK-ERK pathway to late endosomes. The EMBO journal 270 19177150
1999 Role of PPARgamma in regulating a cascade expression of cyclin-dependent kinase inhibitors, p18(INK4c) and p21(Waf1/Cip1), during adipogenesis. The Journal of biological chemistry 268 10358062
2000 Limited overlapping roles of P15(INK4b) and P18(INK4c) cell cycle inhibitors in proliferation and tumorigenesis. The EMBO journal 225 10880462
2001 Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas. The American journal of pathology 219 11485924
1995 Analysis of a family of cyclin-dependent kinase inhibitors: p15/MTS2/INK4B, p16/MTS1/INK4A, and p18 genes in acute lymphoblastic leukemia of childhood. Blood 171 7606004
2001 Involvement of p21(WAF1/Cip1), p27(Kip1), and p18(INK4c) in troglitazone-induced cell-cycle arrest in human hepatoma cell lines. Hepatology (Baltimore, Md.) 148 11343236
1997 Induction of cell cycle arrest and B cell terminal differentiation by CDK inhibitor p18(INK4c) and IL-6. Immunity 132 9052836
2005 The haploinsufficient tumor suppressor p18 upregulates p53 via interactions with ATM/ATR. Cell 121 15680327
2003 Cleavage of Bax to p18 Bax accelerates stress-induced apoptosis, and a cathepsin-like protease may rapidly degrade p18 Bax. Blood 104 12816867
2005 Hematopoietic stem cell exhaustion impacted by p18 INK4C and p21 Cip1/Waf1 in opposite manners. Blood 102 16234365
1994 Regulation of phosphoprotein p18 in leukemic cells. Cell cycle regulated phosphorylation by p34cdc2 kinase. The Journal of biological chemistry 100 8144611
2006 Single-assay combination of Epstein-Barr Virus (EBV) EBNA1- and viral capsid antigen-p18-derived synthetic peptides for measuring anti-EBV immunoglobulin G (IgG) and IgA antibody levels in sera from nasopharyngeal carcinoma patients: options for field screening. Journal of clinical microbiology 96 16597877
2001 Control of spermatogenesis in mice by the cyclin D-dependent kinase inhibitors p18(Ink4c) and p19(Ink4d). Molecular and cellular biology 94 11287627
1996 Alterations of the p15, p16,and p18 genes in osteosarcoma. Cancer genetics and cytogenetics 92 8603340
2001 Antibacterial, antitumor and hemolytic activities of alpha-helical antibiotic peptide, P18 and its analogs. The journal of peptide research : official journal of the American Peptide Society 87 12005420
2002 CDK inhibitor p18(INK4c) is required for the generation of functional plasma cells. Immunity 86 12196289
2003 Haploinsufficiency of p18(INK4c) sensitizes mice to carcinogen-induced tumorigenesis. Molecular and cellular biology 83 12556487
2009 CDK inhibitor p18(INK4c) is a downstream target of GATA3 and restrains mammary luminal progenitor cell proliferation and tumorigenesis. Cancer cell 81 19411068
1996 The p18 component of the multisynthetase complex shares a protein motif with the beta and gamma subunits of eukaryotic elongation factor 1. FEBS letters 71 8849690
1996 Antisense RNA inhibition of phosphoprotein p18 expression abrogates the transformed phenotype of leukemic cells. Cancer research 65 8640838
2003 Antitumour effect of cyclin-dependent kinase inhibitors (p16(INK4A), p18(INK4C), p19(INK4D), p21(WAF1/CIP1) and p27(KIP1)) on malignant glioma cells. British journal of cancer 64 12698196
2000 Cooperation of p27(Kip1) and p18(INK4c) in progestin-mediated cell cycle arrest in T-47D breast cancer cells. Molecular and cellular biology 64 10713180
2002 Posttranscriptional regulation of p18 and p27 Cdk inhibitor proteins and the timing of oligodendrocyte differentiation. Developmental biology 63 11969268
1998 The crystal structure of H-2Dd MHC class I complexed with the HIV-1-derived peptide P18-I10 at 2.4 A resolution: implications for T cell and NK cell recognition. Immunity 62 9729040
1990 Amino acid sequence and characterization of a heparin-binding neurite-promoting factor (p18) from bovine brain. The Journal of biological chemistry 62 2229039
2012 Free fatty acids block glucose-induced β-cell proliferation in mice by inducing cell cycle inhibitors p16 and p18. Diabetes 61 22338094
1997 Heterochromatin protein HP1Hsbeta (p25beta) and its localization with centromeres in mitosis. Chromosoma 61 9169582
2014 miR-543 and miR-590-3p regulate human mesenchymal stem cell aging via direct targeting of AIMP3/p18. Age (Dordrecht, Netherlands) 53 25465621
1996 Intragenic mutations of the p16(INK4), p15(INK4B) and p18 genes in primary non-small-cell lung cancers. International journal of cancer 53 8631583
2006 Characterization of the Babesia gibsoni P18 as a homologue of thrombospondin related adhesive protein. Molecular and biochemical parasitology 52 16675041
1996 Molecular analysis of the cyclin-dependent kinase inhibitor genes p15INK4b/MTS2, p16INK4/MTS1, p18 and p19 in human cancer cell lines. International journal of cancer 51 8938142
2018 UBE3A-mediated p18/LAMTOR1 ubiquitination and degradation regulate mTORC1 activity and synaptic plasticity. eLife 50 30020076
2010 In silico structural and functional analysis of fragments of the ankyrin repeat protein p18(INK4c). Journal of biomolecular structure & dynamics 49 19916573
2009 P18 is a tumor suppressor gene involved in human medullary thyroid carcinoma and pheochromocytoma development. International journal of cancer 48 18942719
2002 Frequent inactivation of the cyclin-dependent kinase inhibitor p18 by homozygous deletion in multiple myeloma cell lines: ectopic p18 expression inhibits growth and induces apoptosis. Leukemia 48 11840272
1996 Biochemical characterization of p16INK4- and p18-containing complexes in human cell lines. The Journal of biological chemistry 47 8663131
1996 Molecular analysis of the cyclin-dependent kinase inhibitor family: p16(CDKN2/MTS1/INK4A), p18(INK4C) and p27(Kip1) genes in neuroblastomas. Cancer 45 8630967
1996 A p18 mutant defective in CDK6 binding in human breast cancer cells. Cancer research 45 8840966
1995 Structural integrity of the cyclin-dependent kinase inhibitor genes, p15, p16 and p18 in myeloid leukaemias. British journal of haematology 45 7577621
2019 Deficiency of TPPP2, a factor linked to oligoasthenozoospermia, causes subfertility in male mice. Journal of cellular and molecular medicine 44 30680919
2015 Small-molecule inhibitors targeting INK4 protein p18(INK4C) enhance ex vivo expansion of haematopoietic stem cells. Nature communications 43 25692908
1996 Complexity of the erythroid transcription factor NF-E2 as revealed by gene targeting of the mouse p18 NF-E2 locus. Proceedings of the National Academy of Sciences of the United States of America 43 8622968
1996 Homozygous deletions of cyclin-dependent kinase inhibitor genes, p16(INK4A) and p18, in childhood T cell lineage acute lymphoblastic leukemias. Leukemia 43 8637234
2008 Identification of p18 INK4c as a tumor suppressor gene in glioblastoma multiforme. Cancer research 42 18381405
2006 p18 Ink4c and Pten constrain a positive regulatory loop between cell growth and cell cycle control. Molecular and cellular biology 42 16738322
2001 An important role of CDK inhibitor p18(INK4c) in modulating antigen receptor-mediated T cell proliferation. Journal of immunology (Baltimore, Md. : 1950) 42 11544316
1996 Role of the cyclin-dependent kinase 4 and 6 inhibitor gene family p15, p16, p18 and p19 in leukemia and lymphoma. Leukemia & lymphoma 42 9031081
2011 The late endosome/lysosome-anchored p18-mTORC1 pathway controls terminal maturation of lysosomes. Biochemical and biophysical research communications 40 22227194
2010 Downregulation of lamin A by tumor suppressor AIMP3/p18 leads to a progeroid phenotype in mice. Aging cell 40 20726853
2010 MEN-4 and other multiple endocrine neoplasias due to cyclin-dependent kinase inhibitors (p27(Kip1) and p18(INK4C)) mutations. Best practice & research. Clinical endocrinology & metabolism 39 20833334
2004 Reduced expression of cell cycle regulator p18(INK4C) in human hepatocellular carcinoma. Hepatology (Baltimore, Md.) 39 15349907
2012 AIMP3/p18 controls translational initiation by mediating the delivery of charged initiator tRNA to initiation complex. Journal of molecular biology 37 22867704
2013 The lysosomal signaling anchor p18/LAMTOR1 controls epidermal development by regulating lysosome-mediated catabolic processes. Journal of cell science 36 23781028
2008 Synergistic effect of oncogenic RET and loss of p18 on medullary thyroid carcinoma development. Cancer research 36 18316595
2008 Determination of three-dimensional structure and residues of the novel tumor suppressor AIMP3/p18 required for the interaction with ATM. The Journal of biological chemistry 36 18343821
2003 The p18 truncated form of Bax behaves like a Bcl-2 homology domain 3-only protein. The Journal of biological chemistry 36 14681224
2014 p18/LAMTOR1: a late endosome/lysosome-specific anchor protein for the mTORC1/MAPK signaling pathway. Methods in enzymology 35 24377928
2006 A protective immune response is generated in rainbow trout by an OmpH-like surface antigen (P18) of Flavobacterium psychrophilum. Applied and environmental microbiology 35 16820479
1999 Tumor suppressor INK4: comparisons of conformational properties between p16(INK4A) and p18(INK4C). Journal of molecular biology 35 10556039
1991 Regulated expression of p18, a major phosphoprotein of leukemic cells. The Journal of biological chemistry 33 1939149
1990 A gene that encodes for a leukemia-associated phosphoprotein (p18) maps to chromosome bands 1p35-36.1. Genes, chromosomes & cancer 33 2278968
2000 Identification of an alpha-helical epitope region on the PM/Scl-100 autoantigen with structural homology to a region on the heterochromatin p25beta autoantigen using immobilized overlapping synthetic peptides. Journal of molecular medicine (Berlin, Germany) 32 10759029
1997 Parathyroid tumor suppressor on 1p: analysis of the p18 cyclin-dependent kinase inhibitor gene as a candidate. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 32 9286748
1988 Monoclonal antibodies to the human immunodeficiency virus p18 protein cross-react with normal human tissues. AIDS (London, England) 32 2456086
1987 Bacterial metabolism of alpha-pinene: pathway from alpha-pinene oxide to acyclic metabolites in Nocardia sp. strain P18.3. Journal of bacteriology 32 3667521
1993 Expression of the leukemia-associated gene, p18, in normal and malignant tissues; inactivation of expression in a patient with cleaved B cell lymphoma/leukemia. Oncogene 30 8397372
1996 Characterization of p18, a component of the lamin B receptor complex and a new integral membrane protein of the avian erythrocyte nuclear envelope. The Journal of biological chemistry 29 8647873
2009 Expression of p18(INK4C) is down-regulated in human pituitary adenomas. Endocrine pathology 28 19401813
2014 p18, a novel adaptor protein, regulates pulmonary endothelial barrier function via enhanced endocytic recycling of VE-cadherin. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26 25404710
2006 1,25(OH)2Vitamin D3 induces elevated expression of the cell cycle inhibitor p18 in a squamous cell carcinoma cell line of the head and neck. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 26 16918598
2015 P18/Stathmin1 is regulated by miR-31 in ovarian cancer in response to taxane. Oncoscience 25 25897432
2014 High prevalence of Y-box protein-1/p18 fragment in plasma of patients with malignancies of different origin. BMC cancer 25 24443788
2006 Simultaneous downregulation of CDK inhibitors p18(Ink4c) and p27(Kip1) is required for MEN2A-RET-mediated mitogenesis. Oncogene 25 16953232
2003 Suppression of ARG kinase activity by STI571 induces cell cycle arrest through up-regulation of CDK inhibitor p18/INK4c. Oncogene 25 12821941
1993 Envelope protein and p18(IIIB) peptide recognized by cytotoxic T lymphocytes from humans immunized with human immunodeficiency virus envelope. Vaccine 25 7688170
2007 Evaluation of CDKN2C/p18, CDKN1B/p27 and CDKN2B/p15 mRNA expression, and CpG methylation status in sporadic and MEN1-associated pancreatic endocrine tumours. Clinical endocrinology 24 17803708
2000 Frequent loss of 1p32 region but no mutation of the p18 tumor suppressor gene in meningiomas. Journal of neuro-oncology 24 11263500
1998 Structure of the gene encoding the human cyclin-dependent kinase inhibitor p18 and mutational analysis in breast cancer. Biochemical and biophysical research communications 24 9636670
1996 The p16 and p18 tumor suppressor genes in neuroblastoma: implications for drug resistance. Cancer letters 24 8665486
2020 PRMT6 serves an oncogenic role in lung adenocarcinoma via regulating p18. Molecular medicine reports 23 32945431
2003 p18(INK4c) collaborates with other CDK-inhibitory proteins in the regenerating liver. Hepatology (Baltimore, Md.) 23 12668976
1995 Molecular analysis of a family of cyclin-dependent kinase inhibitor genes (p15/MTS2/INK4b and p18/INK4c) in non-small cell lung cancers. Molecular carcinogenesis 23 8519415
2016 CDKIs p18(INK4c) and p57(Kip2) are involved in quiescence of CML leukemic stem cells after treatment with TKI. Cell cycle (Georgetown, Tex.) 21 26985855
2011 Y-box protein-1/p18 fragment identifies malignancies in patients with chronic liver disease. BMC cancer 21 21595987
2005 Tumorigenesis in p27/p53- and p18/p53-double null mice: functional collaboration between the pRb and p53 pathways. Molecular carcinogenesis 21 15584024
2004 Activation of protein kinase C promotes human cancer cell growth through downregulation of p18(INK4c). Oncogene 20 15107819
1997 Analysis of the cyclin-dependent kinase inhibitors p18 and p19 in mantle-cell lymphoma and chronic lymphocytic leukemia. Annals of oncology : official journal of the European Society for Medical Oncology 20 9209645
1987 Purification and properties of alpha-pinene oxide lyase from Nocardia sp. strain P18.3. Journal of bacteriology 20 3667522
2006 Hematopoietic stem cells are not the direct target of spontaneous leukemic transformation in p18(INK4C)-null reconstituted mice. Cancer research 19 16397248
2001 Serological diagnosis of Epstein-Barr virus infection by novel ELISAs based on recombinant capsid antigens p23 and p18. Journal of medical virology 19 11241457
2017 The F1 -ATPase from Trypanosoma brucei is elaborated by three copies of an additional p18-subunit. The FEBS journal 18 29247468
2007 p18(Hamlet) mediates different p53-dependent responses to DNA-damage inducing agents. Cell cycle (Georgetown, Tex.) 18 17700068
1998 Immunological characterization of heterochromatin protein p25beta autoantibodies and relationship with centromere autoantibodies and pulmonary fibrosis in systemic scleroderma. Journal of molecular medicine (Berlin, Germany) 18 9462868
1996 Mutational analysis of the joining regions flanking helix P18 in E. coli RNase P RNA. Journal of molecular biology 18 8676378