XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway

Yamaguchi, Kyoko; Nagai, S.; Ninomiya‐Tsuji, Jun; Nishita, Michiru; Tamai, Katsuyuki; Irie, Kenji; Ueno, Naoto; Nishida, Eisuke; Shibuya, H.; Matsumoto, Kunihiro

doi:10.1093/emboj/18.1.179

Cited by 350 publications

(293 citation statements)

References 42 publications

(79 reference statements)

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“…(26) Moreover, JNK1 not JNK2, has been reported to be involved in BMP2-induced osteoblastic differentiation in MC3T3-L1 cells (27) ; also activated by TAK1, a BMP2-activated kinase, it thereby inhibits TNF-a-induced apoptosis in MCF7 cells. (28,29) These studies indicate that JNK1 is important in BMP2-induced osteoblastic differentiation. However, the exact role and the underlying mechanism mediated by JNK1 to regulate Runx2 expression or activity, which in turn affects osteoblastic differentiation, are unclear.…”

Section: Introductionmentioning

confidence: 88%

c-Jun N-terminal kinase 1 negatively regulates osteoblastic differentiation induced by BMP2 via phosphorylation of Runx2 at Ser104

Huang¹,

Lin²,

Chao³

et al. 2012

Journal of Bone and Mineral Research

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Runx2 plays a crucial role in osteoblastic differentiation, which can be upregulated by bone morphogenetic proteins 2 (BMP2). Mitogenactivated protein kinase (MAPK) cascades, such as extracellular signal-regulated kinase (ERK) and p38, have been reported to be activated by BMP2 to increase Runx2 activity. The role of cjun-N-terminal kinase (JNK), the other kinase of MAPK, in osteoblastic differentiation has not been well elucidated. In this study, we first showed that JNK1 is activated by BMP2 in multipotent C2C12 and preosteoblastic MC3T3-E1 cell lines. We then showed that early and late osteoblastic differentiation, represented by ALP expression and mineralization, respectively, are significantly enhanced by JNK1 loss-of-function, such as treatment of JNK inhibitor, knockdown of JNK1 and ectopic expression of a dominant negative JNK1 (DN-JNK1). Consistently, BMP2-induced osteoblastic differentiation is reduced by JNK1 gain-offunction, such as enforced expression of a constitutively active JNK1 (CA-JNK1). Most importantly, we showed that Runx2 is required for JNK1-mediated inhibition of osteoblastic differentiation, and identified Ser104 of Runx2 is the site phosphorylated by JNK1 upon BMP2 stimulation. Finally, we found that overexpression of the mutant Runx2 (Ser104Ala) stimulates osteoblastic differentiation of C2C12 and MC3T3-E1 cells to the extent similar to that achieved by overexpression of wild-type (WT) Runx2 plus JNK inhibitor treatment. Taken together, these data indicate that JNK1 negatively regulates BMP2-induced osteoblastic differentiation through phosphorylation of Runx2 at Ser104. In addition, unraveling these mechanisms may help to develop new strategies in enhancing osteoblastic differentiation and bone formation. ß

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Section: Introductionmentioning

confidence: 88%

c-Jun N-terminal kinase 1 negatively regulates osteoblastic differentiation induced by BMP2 via phosphorylation of Runx2 at Ser104

Huang¹,

Lin²,

Chao³

et al. 2012

Journal of Bone and Mineral Research

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“…3) (Yamaguchi et al, 1995). The upstream activator of TAK1, TAB1 (Shibuya et al, 1996), may be linked to receptor activation via HPK1 or Xlinked inhibitor of apoptosis (XIAP) in case of TGF-b or BMP, respectively (Wang et al, 1997;Yamaguchi et al, 1999). Recently, ARTS, apoptosis-related protein in the TGF-b signaling pathway (Larisch et al, 2000), a protein belonging to the septin family, was found to enhance cell death by TGF-b.…”

Section: Regulation Of Apoptosis By Smadsmentioning

confidence: 99%

Regulation of cell proliferation by Smad proteins

Dijke

Goumans

Itoh

2002

Journal Cellular Physiology

395

275

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Transforming growth factor-b (TGF-b) family members which include TGF-bs, activins, and bone morphogenetic proteins (BMPs) regulate a broad spectrum of biological responses on a large variety of cell types. TGF-b family members initiate their cellular responses by binding to distinct receptors with intrinsic serine/ threonine kinase activity and activation of speci®c downstream intracellular effectors termed Smad proteins. Smads relay the signal from the cell membrane to the nucleus, where they affect the transcription of target genes. Smad activation, subcellular distribution, and stability have been found to be intricately regulated and a broad array of transcription factors have been identi®ed as Smad partners. Important activities of TGF-b are its potent anti-mitogenic and pro-apoptotic effects that, at least in part, are mediated via Smad proteins. Escape from TGF-b/ Smad-induced growth inhibition and apoptosis is frequently observed in tumors. Certain Smads have been found to be mutated in speci®c types of cancer and gene ablation of particular Smads in mice has revealed increased rate of tumorigenesis. In late stage tumors, TGF-b has been shown to function as a tumor promoter. TGFb can stimulate the de-differentiation of epithelial cells to malignant invasive and metastatic ®broblastic cells. Interestingly, TGF-b may mediate these effects directly on tumor cells via subverted Smad-dependent and/or Smad-independent pathways.

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“…This interaction appears to be mediated through the RING domain of D-IAPs, but its functional consequence has not been determined. In a different system, XIAP binds directly to BMP receptor and its downstream signaling molecule TAB1, an activator of a MAP kinase kinase kinase family member named TAK1 [21]. The activation of TAB1-TAK1 promotes ventral mesoderm formation in early Xenopus embryos, which is enhanced by overexpression of wild type XIAP and blocked by expression of an N-terminal truncated XIAP [21].…”

Section: Iaps and Signaling Of Membrane Receptorsmentioning

confidence: 99%

The IAP family: endogenous caspase inhibitors with multiple biological activities

2000

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IAPs (inhibitors of apoptosis) are a family of proteins containing one or more characteristic BIR domains. These proteins have multiple biological activities that include binding and inhibiting caspases, regulating cell cycle progression, and modulating receptor-mediated signal transduction. Our recent studies found the IAP family members XIAP and c-IAP1 are ubiquitinated and degraded in proteasomes in response to apoptotic stimuli in T cells, and their degradation appears to be important for T cells to commit to death. In addition to three BIR domains, each of these IAPs also contains a RING finger domain. We found this region confers ubiquitin protease ligase (E3) activity to IAPs, and is responsible for the auto-ubiquitination and degradation of IAPs after an apoptotic stimulus. Given the fact that IAPs can bind a variety of proteins, such as caspases and TRAFs, it will be of interest to characterize potential substrates of the E3 activity of IAPs and the effects of ubiquitination by IAPs on signal transduction, cell cycle, and apoptosis.

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XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway

Cited by 350 publications

References 42 publications

c-Jun N-terminal kinase 1 negatively regulates osteoblastic differentiation induced by BMP2 via phosphorylation of Runx2 at Ser104

c-Jun N-terminal kinase 1 negatively regulates osteoblastic differentiation induced by BMP2 via phosphorylation of Runx2 at Ser104

Regulation of cell proliferation by Smad proteins

The IAP family: endogenous caspase inhibitors with multiple biological activities

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