MMTV Env encodes an ITAM responsible for transformation of mammary epithelial cells in three-dimensional culture

Katz, Elad; Lareef, Mohamed H.; Rassa, John C.; Grande, Shannon; King, Leslie B.; Russo, José; Ross, Susan R.; Monroe, John G.

doi:10.1084/jem.20041471

Cited by 104 publications

(137 citation statements)

References 48 publications

(80 reference statements)

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“…With respect to their average score, the acinar structure of cells expressing MIGR was very similar to wild-type NMuMG cells (data not shown). MAHB-expressing NMuMG cells developed depolarized acini (Figure 2b), similar to what was seen upon expression of the Env protein of MMTV (Katz et al, 2005). The population of MAHB-expressing acini as a whole were significantly (Po0.0001) more abnormal than those expressing GFP alone ( Figure 2b).…”

Section: Resultssupporting

confidence: 69%

“…Specifically, we showed that NMuMG cells expressing the viral ITAM-containing protein MMTV Env exhibited several hallmarks of transformation, including depolarized 3D morphology, sensitivity to apoptosis induced by TRAIL or TNFa, and downregulation of E-cadherin and Keratin-18 (Katz et al, 2005). The ability of Env to transform mammary epithelial cells was dependent on an intact ITAM.…”

Section: Introductionmentioning

confidence: 97%

“…However, since their identification, it has been noted that a number of oncogenic viruses encode transmembrane ITAMcontaining proteins. These proteins include EpsteinBarr virus (EBV) LMP2A, murine mammary tumor virus (MMTV) Env, and Kaposi's sarcoma-associated herpesvirus (KSHV) K1 (Caldwell et al, 1998;Lee et al, 1998a;Katz et al, 2005). Studies of signaling by LMP2A (Longnecker et al, 1991;Caldwell et al, 1998;Swart et al, 2000) and K1 (Lee et al, 1998a;Lagunoff et al, 1999) in B cells suggests that these ITAMs are capable of signaling in a manner similar to traditional cellular ITAMs.…”

Section: Introductionmentioning

confidence: 99%

“…We recently identified an ITAM associated with the Env protein of MMTV and established the ability of Env to transform NMuMG murine mammary epithelial cells (MECs) in three-dimensional (3D) Matrigel cultures by an ITAM/Syk-dependent pathway (Katz et al, 2005). Specifically, we showed that NMuMG cells expressing the viral ITAM-containing protein MMTV Env exhibited several hallmarks of transformation, including depolarized 3D morphology, sensitivity to apoptosis induced by TRAIL or TNFa, and downregulation of E-cadherin and Keratin-18 (Katz et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Cellular ITAM-containing proteins are oncoproteins in nonhematopoietic cells

et al. 2005

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Immunoreceptor tyrosine-based activation motifs (ITAMs) are involved in the transduction of signals necessary for activation, differentiation, and survival in hematopoietic cells. Several viruses have been shown to encode ITAM-containing transmembrane proteins. Although expression of these viral proteins has in some cases been shown to transform nonhematopoietic cells, a causal role for a functional ITAM in this process has not been elucidated. To examine the potential transforming properties of ITAM-containing proteins, a recombinant protein consisting of ITAM-containing cytoplasmic regions of the B-cell antigen receptor was expressed in immortalized murine mammary epithelial and fibroblast cells. Mammary epithelial cells expressing this construct exhibited depolarized morphology in three-dimensional cultures. This transformed phenotype was characterized by a loss of anchorage dependence and hallmarks of epithelial to mesenchymal transition. Fibroblasts expressing this ITAM construct also lost contact inhibition and anchorage dependence. The transformed phenotype seen in both cell types was abrogated upon tyrosine to phenylalanine substitutions of the ITAMs. Inhibition of Syk tyrosine kinase, which associates with the ITAM, also prevented cell transformation. Our results indicate that expression of a nonviral ITAM-containing protein is sufficient for cell transformation. Despite lacking intrinsic enzymatic activity, ITAM-containing proteins can function as potent oncoproteins by scaffolding downstream mediators.

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Section: Resultssupporting

confidence: 69%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cellular ITAM-containing proteins are oncoproteins in nonhematopoietic cells

et al. 2005

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“…LMP2A and bovine leukemia virus gp 30 were first shown to issue ITAM-dependent signals in T cells (Beaufils et al, 1993). Some functions of the ITAM-containing viral proteins may relate to tumorigenicity, such as survival signalling by activation of the PI3K-Akt pathway by LMP2A and KSHV K1 (Scholle et al, 2000;Swart et al, 2000;Tomlinson and Damania, 2004) and stimulation of cellular migration and invasiveness by LMP2A and MMTV env (Katz et al, 2005;Lu et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

The Shb signalling scaffold binds to and regulates constitutive signals from the Epstein–Barr virus LMP2A membrane protein

et al. 2007

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The Epstein-Barr virus latency-associated membrane protein LMP2A has been shown to activate the survival kinase Akt in epithelial and B cells in a phosphoinositide 3-kinase-dependent fashion. In this study, we demonstrate that the signalling scaffold Shb associates through SH2 and PTB domain interactions with phosphorylated tyrosine motifs in the LMP2A N-terminal tail. Additionally, we show that mutation of tyrosines in these motifs as well as shRNA-mediated downregulation of Shb leads to a loss of constitutive Akt-activation in LMP2A-expressing cells. Furthermore, utilization by Shb of the LMP2A ITAM motif regulates stability of the Syk tyrosine kinase in LMP2A-expressing cells. Our data set the precedent for viral utilization of the Shb signalling scaffold and implicate Shb as a regulator of LMP2A-dependent Akt activation.

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KARAP/DAP12/TYROBP: three names and a multiplicity of biological functions

2005

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The signaling adaptor protein KARAP/DAP12/TYROBP (killer cell activating receptorassociated protein / DNAX activating protein of 12 kDa / tyrosine kinase binding protein) belongs to the family of transmembrane polypeptides bearing an intracytoplasmic immunoreceptor tyrosine-based activation motif (ITAM). This adaptor, initially characterized in NK cells, is associated with multiple cell-surface activating receptors expressed in both lymphoid and myeloid lineages. We review here the main features of KARAP/DAP12, describing findings from its identification to recently published data, showing its involvement in a broad array of biological functions. KARAP/DAP12 is a wiring component for NK cell anti-viral function (e.g. mouse cytomegalovirus via its association with mouse Ly49H) and NK cell anti-tumoral function (e.g. via its association with mouse NKG2D or human NKp44). KARAP/DAP12 is also involved in inflammatory reactions via its coupling to myeloid receptors, such as the triggering receptors expressed by myeloid cells (TREM) displayed by neutrophils, monocytes/ macrophages and dendritic cells. Finally, bone remodeling and brain function are also dependent upon the integrity of KARAP/DAP12 signals, as shown by the analysis of KARAP/DAP12-deficient mice and KARAP/DAP12-deficient Nasu-Hakola patients. IntroductionPolypeptides that bear at least one immunoreceptor tyrosine-based activation motif (ITAM; YxxL-x 7 -YxxL) in their intracytoplasmic domain constitute family of various signaling molecules ( Fig. 1A and B). ITAM were first identified in the immune system, where they are required for the expression and signaling of several activating immunoreceptors, thus playing a key role in immune responses. ITAM-bearing proteins can also be detected in non-hematopoietic tissues, such as the brain, and they can also be produced by several viruses (Fig. 1A and B). The latest ITAM-bearing polypeptide to be identified [1][2][3][4][5] protein (TYROBP); here we refer to it as KARAP/DAP12. As previously described for other ITAM-bearing polypeptides, tyrosine residues present in KARAP/DAP12 ITAM, once phosphorylated, are both required for the recruitment and the activation of Syk and ZAP70, which are SH2-domain-containing protein tyrosine kinases (PTK) [3]. KARAP/DAP12 transcripts are present in bony fishes, rodents, swine and humans, showing the broad conservation of this signaling component in vertebrates [2, 3, 6, 7]. KARAP/DAP12 expression is detectable in both lymphoid and myeloid cells, where it can associate with several activating immunoreceptors, contributing to several biological functions [8].In this review, we will correlate KARAP/DAP12 broad expression in both hematopoietic and non-hematopoietic tissues with pleiotropic functions of this signaling , protein G1 of hantavirus (sequence indicated corresponds to substrain NY1, but G1 proteinITAM sequences of several other hantavirus substrains' have also been reported) [59]. All the ITAM motifs reported here, except for viral molecules, are derived from human sequenc...

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MMTV Env encodes an ITAM responsible for transformation of mammary epithelial cells in three-dimensional culture

Cited by 104 publications

References 48 publications

Cellular ITAM-containing proteins are oncoproteins in nonhematopoietic cells

Cellular ITAM-containing proteins are oncoproteins in nonhematopoietic cells

The Shb signalling scaffold binds to and regulates constitutive signals from the Epstein–Barr virus LMP2A membrane protein

KARAP/DAP12/TYROBP: three names and a multiplicity of biological functions

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