Kinase Family TGM
Kinase Classification: Group SAPPK: Family TGM
Tissue Transglutaminase 2 (TGM2) is a multi-functional protein that has been reported in human to phosphorylate several proteins, including p53, Histones and Rb. Its other functions including cross linking of proteins via Glu and Lys residues, acting as a GPCR and possibly as a protein disulfide isomerase.
Evidence for Kinase Activity
TGM2 was first identified as a protein kinase by the Murphy group, by purification of an IGFBP3 kinase activity from membrane fractions of a cell line [1]. Affinity purification of TGM2 from human, guinea pig or bacculovirus-driven insect expression all had IGFBP3 kinase activity. Inhibitors of the cross-linking activity of TGM2 (cystamine and monodansyl cadaverine) inhibited the kinase activity. Phopshorylation was on Ser and Thr. The immunopurification method used leaves open the possibility that the kinase activity was due to a tightly bound co-purifying protein.
The same group showed that immunopurified TGM2 could also phosphorylate as well as cross-link several histones [2], using insect-produced protein. This paper reports (but does not show) that the kinase activity is also seen in E. coli-produced protein and that the kinase activity migrates along with TG2 in an in-gel kinase activity, decreasing the likelihood that the kinase activity is a contaminant. TGM2 was also seen to phosphorylate p53 on Ser [3], and to phosphorylate Rb protein [4]. Phosphorylation of TGM2 by PKA increased its kinase activity but reduced its transamidating activity.
TGM2 was previously reported to bind hydrolyze both GTP and ATP [5], and this activity was mapped to the first 185 AA, consisting of the Transglutaminase_N domain and about 65 more AA.
Domain Structure
TGM2 has four major conserved regions: A Transglutaminase_N N-terminal domain of about 120 AA, a transgluaminase core region in the middle, and two Transglutaminase_C Ig-like domains at the C terminus. TGM4 and TGM7 lack the second Transglutaminase_C domain.
Evolution
Human paralogs of TGM2 are TGM1 (TGK), TGM3 (TGE), TGM4, TGM5, TGM6 (TGY), TGM7 (TGMZ), Band 4.2 protein (EPB42), and coagulation factor XIII A (F13A1). F13A1 has been claimed to also have protein kinase activity, though no data was shown [3].
Homologs of the full-length protein are found throughout holozoa, and the core transglutaminase domain is found in some bacteria and archaea, but not in protists or plants.
