Protein Kinase D1 Phosphorylates HDAC7 and Induces Its Nuclear Export after T-cell Receptor Activation

Parra, Maribel; Kasler, Herbert G.; McKinsey, Timothy A.; Olson, Eric N.; Verdin, Eric

doi:10.1074/jbc.m413396200

Cited by 128 publications

(128 citation statements)

References 38 publications

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“…This suggests that HDAC7 acts as a focal point for multiple signaling pathways. Consistent with this notion, the T cell receptor has been shown to regulate apoptosis in thymocytes via phosphorylation and nuclear export of HDAC7 (28,29).…”

Section: Discussionmentioning

confidence: 69%

“…PKD1, also known as protein kinase C (PKC ), is the founding member of a the PKD family, which also includes PKD2 and PKD3/PKC (30). PKD1 has been identified as class IIa HDAC export kinase in cardiomyocytes and thymocytes (29,31,32). PKD has been implicated in diverse processes, such as, vesicular transport, metastasis, immune responses, apoptosis, and cell proliferation (30).…”

Section: Discussionmentioning

confidence: 99%

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Control of endothelial cell proliferation and migration by VEGF signaling to histone deacetylase 7

Wang

Parra

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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218

190

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VEGF has been shown to regulate endothelial cell (EC) proliferation and migration. However, the nuclear mediators of the actions of VEGF in ECs have not been fully defined. We show that VEGF induces the phosphorylation of three conserved serine residues in histone deacetylase 7 (HDAC7) via protein kinase D, which promotes nuclear export of HDAC7 and activation of VEGF-responsive genes in ECs. Expression of a signal-resistant HDAC7 mutant protein in ECs inhibits proliferation and migration in response to VEGF. These results demonstrate that phosphorylation of HDAC7 serves as a molecular switch to mediate VEGF signaling and endothelial function.angiogenesis ͉ PKD1 ͉ MEF2 ͉ class II HDAC

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Control of endothelial cell proliferation and migration by VEGF signaling to histone deacetylase 7

Wang

Parra

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

218

190

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“…2B and 5). Taken together, these data suggest that the kinases including CaMKs and PKD [21,22,25] phosphorylate class IIa HDACs and sequester them in the cytoplasm, blocking their nuclear import. One possible mechanism is that Ser 178 (14-3-3 binding site) is closely adjacent to the NLS (amino acids 183-191) and association of phosphorylated HDAC7 with 14-3-3s may mask recognition of the NLS by importin a [30].…”

Section: Discussionmentioning

confidence: 80%

“…In addition to CaMKs, protein kinase D family kinases and Mirk/dyrk1B also play a role in subcellular distribution of class IIa HDACs [21][22][23][24][25]. Nonetheless, it is not clear whether phosphorylation of these conserved residues is essential for nuclear export of HDAC7.…”

Section: Introductionmentioning

confidence: 99%

CRM1 mediates nuclear export of HDAC7 independently of HDAC7 phosphorylation and association with 14‐3‐3s

Gao

Lam

et al. 2006

FEBS Letters

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CRM1, 14-3-3 proteins, and CaMK play important roles in trafficking of HDAC7, but the interplay between these proteins in this process is not clearly understood. Here, we show that CRM1 is capable of promoting cytoplasmic localization of wild-type and mutant HDAC7 (S178A/S344A/S479A), which is normally found in the nucleus. Using phospho-specific antibodies to HDAC7, we demonstrate that CaMK I promotes phosphorylation of S178, S344, and S479 of HDAC7. We also show that endogenous S178-phosphorylated HDAC7 is localized in both the nucleus and the cytoplasm, whereas S344-and S479-phosphorylated HDAC7 are exclusively localized in the nucleus. An HDAC7 mutant, S178E/S344E/S479E, which lost the ability to bind 14-3-3s, is localized in both the nucleus and the cytoplasm. Furthermore, the nuclear export of S178E/S344E/ S479E is inhibited by LMB, but is enhanced by the CRM1. Taken together, these results strongly suggest that CRM1 mediated-nuclear export of HDAC7 is independent of HDAC7 phosphorylation and its association with 14-3-3s.

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“…This leads to a loss of transcription repression and a MEF2D-dependent induction of Nur77 expression and apoptosis. 60,61 Two possible outcomes of caspase-8-mediated HDAC7 cleavage in thymocytes can be envisaged. First, cleavage could promote expression of Nur77 and feed forward to enhance apoptosis.…”

Section: Downstream Moleculesmentioning

confidence: 99%

Role of caspase-8 in thymus function

et al. 2013

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The thymus is the primary organ responsible for de novo generation of immunocompetent T cells that have a diverse repertoire of antigen recognition. During the developmental process, 98% of thymocytes die by apoptosis. Thus apoptosis is a dominant process in the thymus and occurs through either death by neglect or negative selection or through induction by stress/aging. Caspase activation is an essential part of the general apoptosis mechanism, and data suggest that caspases may have a role in negative selection; however, it seems more probable that caspase-8 activation is involved in death by neglect, particularly in glucocorticoid-induced thymocyte apoptosis. Caspase-8 is active in double-positive (DP) thymocytes in vivo and can be activated in vitro in DP thymocytes by T-cell receptor (TCR) crosslinking to induce apoptosis. Caspase-8 is a proapoptotic member of the caspase family and is considered an initiator caspase, which is activated upon stimulation of a death receptor (e.g., Fas), recruitment of the adaptor molecule FADD, and recruitment and subsequent processing of procaspase-8. The main role of caspase-8 seems to be pro-apoptotic and, in this review, we will discuss about the involvement of caspase-8 in (1) TCR-triggered thymic apoptosis; (2) death receptor-mediated thymic apoptosis; and (3) glucocorticoid-induced thymic apoptosis. Regarding TCR triggering, caspase-8 is active in medullary, semi-mature heat-stable antigen hi (HAS hi SP) thymocytes as a consequence of strong TCR stimulation. The death receptors Fas, FADD, and FLIP are involved upstream of caspase-8 activation in apoptosis; whereas, Bid and HDAC7 are involved downstream of caspase-8. Finally, caspase-8 is involved in glucocortocoid-induced thymocyte apoptosis through an activation loop with the protein GILZ. GILZ activates caspase-8, promoting GILZ sumoylation and its protection from proteasomal degradation.

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Protein Kinase D1 Phosphorylates HDAC7 and Induces Its Nuclear Export after T-cell Receptor Activation

Cited by 128 publications

References 38 publications

Control of endothelial cell proliferation and migration by VEGF signaling to histone deacetylase 7

Control of endothelial cell proliferation and migration by VEGF signaling to histone deacetylase 7

CRM1 mediates nuclear export of HDAC7 independently of HDAC7 phosphorylation and association with 14‐3‐3s

Role of caspase-8 in thymus function

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