ERK7 is a negative regulator of protein secretion in response to amino-acid starvation by modulating Sec16 membrane association

Zacharogianni, Margarita; Kondylis, Vangelis; Tang, Yang; Farhan, Hesso; Xanthakis, Despina; Fuchs, Florian; Boutros, Michael; Rabouille, Cathérine

doi:10.1038/emboj.2011.253

Cited by 102 publications

(141 citation statements)

References 74 publications

(136 reference statements)

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“…giERK2 lacks the extended C-terminal domain found in ERK7 and may not be regulated in the same manner, and yet in vitro kinase assays have shown that giERK2 is much more active than giERK1 (48). In other eukaryotes, ERK7 kinases have been shown to regulate protein secretion and cell proliferation (50,51). Our identification of an actin-ERK2 complex in Giardia and the localization of this kinase in the nucleus and throughout the cell do not exclude potentially conserved function.…”

Section: Discussionmentioning

confidence: 92%

Identification of Obscure yet Conserved Actin-Associated Proteins in Giardia lamblia

Paredez

Nayeri

et al. 2014

Eukaryot Cell

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bConsistent with its proposed status as an early branching eukaryote, Giardia has the most divergent actin of any eukaryote and lacks core actin regulators. Although conserved actin-binding proteins are missing from Giardia, its actin is utilized similarly to that of other eukaryotes and functions in core cellular processes such as cellular organization, endocytosis, and cytokinesis. We set out to identify actin-binding proteins in Giardia using affinity purification coupled with mass spectroscopy (multidimensional protein identification technology [MudPIT]) and have identified >80 putative actin-binding proteins. Several of these have homology to conserved proteins known to complex with actin for functions in the nucleus and flagella. We validated localization and interaction for seven of these proteins, including 14-3-3, a known cytoskeletal regulator with a controversial relationship to actin. Our results indicate that although Giardia lacks canonical actin-binding proteins, there is a conserved set of actin-interacting proteins that are evolutionarily indispensable and perhaps represent some of the earliest functions of the actin cytoskeleton.

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Section: Discussionmentioning

confidence: 92%

Identification of Obscure yet Conserved Actin-Associated Proteins in Giardia lamblia

Paredez

Nayeri

et al. 2014

Eukaryot Cell

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“…a strict COPII-dependent emergence of a secretory flux. Although this study focused the role of mitogens in regulating ERES, others have recently identified in Drosophila a novel response of ERES to amino acid starvation (Zacharogianni et al, 2014), which is distinct from the response to serum starvation reported previously (Zacharogianni et al, 2011). Amino acid starvation results in the formation of 'Sec bodies', where Sec16 and other COPII components are stored.…”

Section: Discussionmentioning

confidence: 97%

Regulation of Sec16 levels and dynamics links proliferation and secretion

Tillmann

Reiterer

Baschieri

et al. 2014

Journal of Cell Science

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We currently lack a broader mechanistic understanding of the integration of the early secretory pathway with other homeostatic processes such as cell growth. Here, we explore the possibility that Sec16A, a major constituent of endoplasmic reticulum exit sites (ERES), acts as an integrator of growth factor signaling. Surprisingly, we find that Sec16A is a short-lived protein that is regulated by growth factors in a manner dependent on Egr family transcription factors. We hypothesize that Sec16A acts as a central node in a coherent feed-forward loop that detects persistent growth factor stimuli to increase ERES number. Consistent with this notion, Sec16A is also regulated by short-term growth factor treatment that leads to increased turnover of Sec16A at ERES. Finally, we demonstrate that Sec16A depletion reduces proliferation, whereas its overexpression increases proliferation. Together with our finding that growth factors regulate Sec16A levels and its dynamics on ERES, we propose that this protein acts as an integrator linking growth factor signaling and secretion. This provides a mechanistic basis for the previously proposed link between secretion and proliferation.

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“…ERK7 undergoes autophosphorylation and is constitutively active 3 . Previous studies in cultured cells have shown that ERK7 is involved in the protection of genomic integrity, response to amino-acid starvation and autophagy [4][5][6] . However, its function in vivo remains largely unknown.…”

mentioning

confidence: 99%

ERK7 regulates ciliogenesis by phosphorylating the actin regulator CapZIP in cooperation with Dishevelled

et al. 2015

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Cilia are essential for embryogenesis and maintenance of homeostasis, but little is known about the signalling pathways that regulate ciliogenesis. Here, we identify ERK7, an atypical mitogen-activated protein kinase, as a key regulator of ciliogenesis. ERK7 is strongly expressed in ciliated tissues of Xenopus embryos. ERK7 knockdown markedly diminishes both the number and the length of cilia in multiciliated cells, and it inhibits the apical migration of basal bodies. Moreover, ERK7 knockdown results in a loss of the apical actin meshwork, which is required for the proper migration of basal bodies. We find that the actin regulator CapZIP, which has been shown to regulate ciliogenesis in a phosphorylation-dependent manner, is an ERK7 substrate, and that Dishevelled, which has also been shown to regulate ciliogenesis, facilitates ERK7 phosphorylation of CapZIP through binding to both ERK7 and CapZIP. Collectively, these results identify an ERK7/Dishevelled/CapZIP axis that regulates ciliogenesis.

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ERK7 is a negative regulator of protein secretion in response to amino-acid starvation by modulating Sec16 membrane association

Cited by 102 publications

References 74 publications

Identification of Obscure yet Conserved Actin-Associated Proteins in Giardia lamblia

Identification of Obscure yet Conserved Actin-Associated Proteins in Giardia lamblia

Regulation of Sec16 levels and dynamics links proliferation and secretion

ERK7 regulates ciliogenesis by phosphorylating the actin regulator CapZIP in cooperation with Dishevelled

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