Molecule Information

General Information of the Molecule (ID: Mol04165)

• Name: Transglutaminase 2 (TGM2) ,Homo sapiens
• Synonyms: Erythrocyte transglutaminase; Heart G alpha(h); Isopeptidase TGM2; Protein G alpha(h); Protein-glutamine deamidase TGM2; Protein-glutamine dopaminyltransferase TGM2; Protein-glutamine histaminyltransferase TGM2; Protein-glutamine noradrenalinyltransferase TGM2; Protein-glutamine serotonyltransferase TGM2; Tissue transglutaminase; Transglutaminase C; Transglutaminase H; Transglutaminase II; Transglutaminase-2
• Molecule Type: Protein
• Gene Name: TGM2
• Gene ID: 7052
• Location: chr20:38127385-38166578[-]
• Sequence:
  MAEELVLERCDLELETNGRDHHTADLCREKLVVRRGQPFWLTLHFEGRNYEASVDSLTFS
  VVTGPAPSQEAGTKARFPLRDAVEEGDWTATVVDQQDCTLSLQLTTPANAPIGLYRLSLE
  ASTGYQGSSFVLGHFILLFNAWCPADAVYLDSEEERQEYVLTQQGFIYQGSAKFIKNIPW
  NFGQFEDGILDICLILLDVNPKFLKNAGRDCSRRSSPVYVGRVVSGMVNCNDDQGVLLGR
  WDNNYGDGVSPMSWIGSVDILRRWKNHGCQRVKYGQCWVFAAVACTVLRCLGIPTRVVTN
  YNSAHDQNSNLLIEYFRNEFGEIQGDKSEMIWNFHCWVESWMTRPDLQPGYEGWQALDPT
  PQEKSEGTYCCGPVPVRAIKEGDLSTKYDAPFVFAEVNADVVDWIQQDDGSVHKSINRSL
  IVGLKISTKSVGRDEREDITHTYKYPEGSSEEREAFTRANHLNKLAEKEETGMAMRIRVG
  QSMNMGSDFDVFAHITNNTAEEYVCRLLLCARTVSYNGILGPECGTKYLLNLNLEPFSEK
  SVPLCILYEKYRDCLTESNLIKVRALLVEPVINSYLLAERDLYLENPEIKIRILGEPKQK
  RKLVAEVSLQNPLPVALEGCTFTVEGAGLTEEQKTVEIPDPVEAGEEVKVRMDLLPLHMG
  LHKLVVNFESDKLKAVKGFRNVIIGPA
• 3D-structure: PDB ID: 3LY6; Classification: Transferase; Method: X-ray diffraction; Resolution: 3.14 Å
• Function: Calcium-dependent acyltransferase that catalyzes the formation of covalent bonds between peptide-bound glutamine and various primary amines, such as gamma-amino group of peptide-bound lysine, or mono- and polyamines, thereby producing cross-linked or aminated proteins, respectively (PubMed:23941696, PubMed:31991788, PubMed:9252372). Involved in many biological processes, such as bone development, angiogenesis, wound healing, cellular differentiation, chromatin modification and apoptosis (PubMed:1683874, PubMed:27270573, PubMed:28198360, PubMed:7935379, PubMed:9252372). Acts as a protein- glutamine gamma-glutamyltransferase by mediating the cross-linking of proteins, such as ACO2, HSPB6, FN1, HMGB1, RAP1GDS1, SLC25A4/ANT1, SPP1 and WDR54 (PubMed:23941696, PubMed:24349085, PubMed:29618516, PubMed:30458214). Under physiological conditions, the protein cross- linking activity is inhibited by GTP; inhibition is relieved by Ca(2+) in response to various stresses (PubMed:18092889, PubMed:7592956, PubMed:7649299). When secreted, catalyzes cross-linking of proteins of the extracellular matrix, such as FN1 and SPP1 resulting in the formation of scaffolds (PubMed:12506096). Plays a key role during apoptosis, both by (1) promoting the cross-linking of cytoskeletal proteins resulting in condensation of the cytoplasm, and by (2) mediating cross-linking proteins of the extracellular matrix, resulting in the irreversible formation of scaffolds that stabilize the integrity of the dying cells before their clearance by phagocytosis, thereby preventing the leakage of harmful intracellular components (PubMed:7935379, PubMed:9252372). In addition to protein cross-linking, can use different monoamine substrates to catalyze a vast array of protein post-translational modifications: mediates aminylation of serotonin, dopamine, noradrenaline or histamine into glutamine residues of target proteins to generate protein serotonylation, dopaminylation, noradrenalinylation or histaminylation, respectively (PubMed:23797785, PubMed:30867594). Mediates protein serotonylation of small GTPases during activation and aggregation of platelets, leading to constitutive activation of these GTPases (By similarity). Plays a key role in chromatin organization by mediating serotonylation and dopaminylation of histone H3 (PubMed:30867594, PubMed:32273471). Catalyzes serotonylation of 'Gln-5' of histone H3 (H3Q5ser) during serotonergic neuron differentiation, thereby facilitating transcription (PubMed:30867594). Acts as a mediator of neurotransmission-independent role of nuclear dopamine in ventral tegmental area (VTA) neurons: catalyzes dopaminylation of 'Gln-5' of histone H3 (H3Q5dop), thereby regulating relapse-related transcriptional plasticity in the reward system (PubMed:32273471). Regulates vein remodeling by mediating serotonylation and subsequent inactivation of ATP2A2/SERCA2 (By similarity). Also acts as a protein deamidase by mediating the side chain deamidation of specific glutamine residues of proteins to glutamate (PubMed:20547769, PubMed:9623982). Catalyzes specific deamidation of protein gliadin, a component of wheat gluten in the diet (PubMed:9623982). May also act as an isopeptidase cleaving the previously formed cross-links (PubMed:26250429, PubMed:27131890). Also able to participate in signaling pathways independently of its acyltransferase activity: acts as a signal transducer in alpha-1 adrenergic receptor-mediated stimulation of phospholipase C-delta (PLCD) activity and is required for coupling alpha-1 adrenergic agonists to the stimulation of phosphoinositide lipid metabolism (PubMed:8943303). .; [Isoform 2]: Has cytotoxic activity: is able to induce apoptosis independently of its acyltransferase activity. .
• Uniprot ID: TGM2_HUMAN
• Ensembl ID: ENSG00000198959
• HGNC ID: HGNC:11778

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Gemcitabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0] [1]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Resistant Drug: Gemcitabine
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Pancreatic cancer [ICD-11: 2C10]
• The Specified Disease: Pancreatic ductal adenocarcinoma
• The Studied Tissue: Pancreas
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.67E-17; Fold-change: 6.28E-01; Z-score: 9.67E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Panc1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• In Vitro Model: Patu-8988 cells; Pancreas; Homo sapiens (Human); CVCL_1846
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: Functional and clinical verification revealed that a higher TGM2 expression is linked with a worse patient survival, an increased IC50 value of gemcitabine, and a higher abundance of tumor-infiltrating macrophages in pancreatic cancer. Mechanistically, we found that increased C-C motif chemokine ligand 2 (CCL2) release mediated by TGM2 contributes to macrophage infiltration into the tumor microenvironment.

References

• Ref 1: Transglutaminases are oncogenic biomarkers in human cancers and therapeutic targeting of TGM2 blocks chemoresistance and macrophage infiltration in pancreatic cancer. Cell Oncol (Dordr). 2023 Oct;46(5):1473-1492.