The amino terminus of polyomavirus middle T antigen is required for transformation

Cook, Donald N.; Hassell, John A.

doi:10.1128/jvi.64.5.1879-1887.1990

Cited by 18 publications

(8 citation statements)

References 50 publications

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“…DnaJ proteins help regulate cellular signaling pathways, including those involving pp60 Src tyrosine kinases, the transcrip- tional activator p53, and steroid hormone receptors (4,8,37,56,69), and the T antigens intercede in these pathways by associating with effector proteins such as pp60 Src , c-Yes, c-Fyn, Shc, Grb2, PP2A, the 14.3-3 proteins, pRb, p107, p130, p300/ CBP, p53, TEF-1, TBP, AP1, and AP2 (3,6,11,16,21,22,27,32,38,47,49,74,80). The amino-terminal domain is also important for transactivation and cell transformation (9,14,15,20,39,41,43,45,54,55,67,70,73,74,84,86). Thus, it is readily understandable how a DnaJ domain activity within the primary structure of the T antigens might be utilized: the DnaJ domain could help assemble or disassemble T antigen complexes, perhaps in a fashion analogous to the cis-acting DnaJ domain in the auxilin protein (77).…”

Section: Discussionmentioning

confidence: 99%

“…There is substantial evidence for the involvement of the amino-terminal domain of middle T antigen in its transforming function (15,26,73), and this can be rationalized by the requirement of the extreme amino-terminal sequences for association with protein phosphate 2A and pp60 Src (5,26). Surprisingly, mutations within the highly conserved HPDK element of the DnaJ motif have little effect upon this association or upon the transformation of NIH 3T3 cells as measured by focus formation (5,26).…”

Section: Discussionmentioning

confidence: 99%

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Tiny T antigen: an autonomous polyomavirus T antigen amino-terminal domain

Riley

Yoo

Mda

et al. 1997

J Virol

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Three mRNAs from the murine polyomavirus early region encode the three well-characterized tumor antigens. We report the existence of a fourth alternatively spliced mRNA which encodes a fourth tumor antigen, tiny T antigen, which comprises the amino-terminal domain common to all of the T antigens but is extended by six unique amino acid residues. The amount of tiny T antigen in infected cells is small because of its short half-life. Tiny T antigen stimulates the ATPase activity of Hsc70, most likely because of its DnaJ-like motif. The common amino-terminal domain may interface with chaperone complexes to assist the T antigens in carrying out their diverse functions of replication, transcription, and transformation in the appropriate cellular compartments. The small, middle, and large T antigens expressed by the murine polyomavirus (muPy) are formed of a common aminoterminal sequence juxtaposed to unique carboxy-terminal sequences (33, 65). Such parsimony in protein structures reflects the pattern of viral gene expression, for the T antigens are encoded by a single primary transcript containing two splice acceptor and two splice donor sites (76) (Fig. 1), creating the potential of four separate mRNAs. Three of these RNAs encode the small, middle, and large T antigens. The fourth mRNA, heretofore undetected, should encode a protein with the T antigen common amino-terminal domain extended by six residues. Here, we report the detection of this mRNA and the partial characterization of the protein it encodes (tiny T antigen). Genetic and biochemical evidence indicates the muPy T antigen common amino-terminal domain is required for cell transformation and promotes small and middle T antigen association with PP2A, c-Src, and perhaps other proteins (5, 26, 73). These cellular signal transducers strongly influence viral DNA replication, transcription, and translation; consequently, the T antigen common amino-terminal domain must contribute to virtually all aspects of the virus life cycle. Sequence homology between the T antigen amino-terminal domain and DnaJ proteins has been noted (36). DnaJ proteins modulate the ATPase activity of the hsp70 class of chaperones, and we observe that tiny T antigen expressed in Escherichia coli and purified to near homogeneity exhibits such a stimulatory activity in vitro. This activity within the T antigen amino-terminal domain very likely contributes to the functions of the T antigens by promoting their interactions with cellular chaperones. MATERIALS AND METHODS Cells and viruses. NIH 3T3, 3T6, and COS1 cells were obtained from the American Type Culture Collection. Polyomavirus transformed MOP-3T3 and MOP-3T6 cells were obtained from John Hassell (McMaster University, Ontario, Canada). Whole mouse embryo (WME) cells were prepared from outbred mice as described previously (24). All cells were grown in Dulbecco's modified Eagle's medium (low glucose) supplemented with 10% fetal calf serum.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tiny T antigen: an autonomous polyomavirus T antigen amino-terminal domain

Riley

Yoo

Mda

et al. 1997

J Virol

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“…23 The d2-4 Py virus mutant (mutation common to all T-Antigens), lacking three amino acid residues (DRV) at the N-terminus does not bind Taz 23 and some other PyMT-signaling complex members, and is inactive in transforming cells. [24][25][26] Recently it was reported that Taz and Yap dominantly regulate the localization of the Shp2 phosphatase through direct physical interaction. 27 It also was reported that Shp2 decreases PyMT transformation of mouse fibroblasts, 28 at least in part due to its function in dephosphorylating and inactivating STAT3.…”

Section: Introductionmentioning

confidence: 99%

The polyomavirus middle T-antigen oncogene activates the Hippo pathway tumor suppressor Lats in a Src-dependent manner

et al. 2014

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The polyomavirus middle T antigen (PyMT) is an oncogene that activates the non-receptor tyrosine kinase, c-Src, and physically interacts with Taz (WWTR1). Taz is a pro-oncogenic transcription coactivator of the Tead transcription factors. The Hippo tumor suppressor pathway activates the kinase Lats, which phosphorylates Taz, leading to its nuclear exclusion and blunting Tead coactivation. We found that Taz was required for transformation by PyMT, but counter-intuitively, Taz was exclusively cytoplasmic in the presence of PyMT. We demonstrate that in the presence of PyMT, wild-type Taz was phosphorylated by Lats, in a Src-dependent manner. Consistently, a Lats refractory Taz mutant did not undergo cytoplasmic retention by PyMT. We show that Yap, the Taz paralog, and Shp2 phosphatase were nuclear excluded as well. Our findings describe a noncanonical activation of Lats, and an unprecedented Tead-independent role for Taz and Yap in viral-mediated oncogenesis.

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“…Mutation of a conserved valine (V4D), two pairs of dileucines (LL13,14AA and LL16,17AA), or a conserved tryptophan-glycine (WG24,25AA) each resulted in a protein which could not associate with PP2A. The V4D mutant was previously shown to be transformation defective, presumably because of its failure to interact with pp60 c-src (8). The arginines at positions 7 and 21 and the single leucine at position 19 do not appear to be required for complex formation, although they are conserved among the three viruses.…”

Section: Discussionmentioning

confidence: 99%

“…We deleted both conserved regions, removing amino acids 2 to 7 and 13 to 25. The point mutant Val4Asp, a nontransforming mutant of MT, was described previously (8). In addition, we mutated the adjacent conserved leucine 5 to a glutamic acid and the conserved arginine at position 7 to a methionine.…”

Section: Mutagenesis Of Polyomavirus Mtmentioning

confidence: 99%

Amino-terminal regions of polyomavirus middle T antigen are required for interactions with protein phosphatase 2A

Glenn

Eckhart

1995

J Virol

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Polyomavirus middle T antigen (MT) is the major transforming protein of the virus. It functions through interactions with a number of cellular proteins involved in cell proliferation. MT forms complexes with protein phosphatase 2A (PP2A), pp60 c-src , phosphatidylinositol 3-kinase, and Shc. We introduced both deletion and point mutations into three regions of MT and examined their ability to associate with PP2A and pp60 c-src. The first 25 amino acid residues of MT are required for association with PP2A and pp60 c-src. Amino acids 105 to 111, comprising the sequence Cys-Arg-Met-Pro-Leu-Thr-Cys, is also required for complex formation between MT and PP2A. However, the sequence Asp-Lys-Gly-Gly (amino acids 44 to 47), also found in the B subunit of PP2A, is dispensable for complex formation between MT and PP2A. We find a strict correlation between the ability of MT to associate with PP2A and the ability of MT to associate with pp60 c-src. One mutant, L5E, associates with a phosphatase other than PP2A, pp60 c-src , and phosphatidylinositol 3-kinase in a manner similar to that of wild-type MT yet is reduced in its transforming ability on NIH 3T3 cells.

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The amino terminus of polyomavirus middle T antigen is required for transformation

Cited by 18 publications

References 50 publications

Tiny T antigen: an autonomous polyomavirus T antigen amino-terminal domain

Tiny T antigen: an autonomous polyomavirus T antigen amino-terminal domain

The polyomavirus middle T-antigen oncogene activates the Hippo pathway tumor suppressor Lats in a Src-dependent manner

Amino-terminal regions of polyomavirus middle T antigen are required for interactions with protein phosphatase 2A

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