Src Regulates Golgi Structure and KDEL Receptor-dependent Retrograde Transport to the Endoplasmic Reticulum

Bard, Frédéric; Mazelin, Laetitia; Péchoux-Longin, Christine; Malhotra, Vivek; Jurdic, Pierre

doi:10.1074/jbc.m302221200

Cited by 99 publications

(101 citation statements)

References 24 publications

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“…This model is supported by the compact Golgi morphology that we observed in cells treated with PP2 and that others have observed in cells lacking Src kinase family members, such as SYF −/− cells (30). Thus, in normal cells, Src activity is expected to vesiculate the Golgi during a secretory stimulus.…”

Section: Discussionsupporting

confidence: 68%

Src kinase regulates the integrity and function of the Golgi apparatus via activation of dynamin 2

Weller

Capitani²,

Cao

et al. 2010

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

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The size and integrity of the Golgi apparatus is maintained via a tightly controlled regulation of membrane traffic using a variety of different signaling and cytoskeletal proteins. We have recently observed that activation of c-Src has profound effects on Golgi structure, leading to dramatically vesiculated cisternae in a variety of cell types. As the large GTPase dynamin (Dyn2) has been implicated in Golgi vesiculation during secretion, we tested whether inhibiting Dyn2 activity by expression of a Dyn2K44A mutant or siRNA knockdown could attenuate active Src-induced Golgi fragmentation. Indeed, these perturbations attenuated fragmentation, and expression of a Dyn2Y(231/597)F mutant protein that cannot be phosphorylated by Src kinase had a similar effect . Finally, we find that Dyn2 is markedly phosphorylated during the transit of VSV-G protein through the TGN whereas expression of the Dyn2Y(231/597)F mutant significantly reduces exit of the nascent protein from this compartment. These findings demonstrate that activation of Dyn2 by Src kinase regulates Golgi integrity and vesiculation during the secretory process.

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Section: Discussionsupporting

confidence: 68%

Src kinase regulates the integrity and function of the Golgi apparatus via activation of dynamin 2

Weller

Capitani²,

Cao

et al. 2010

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

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“…58 Interestingly, it was also demonstrated that the exogenous expression of the constitutive-active Src (E378G) in the SYF cells affected the distribution of some if not all Golgi-specific proteins. 58 Thus, it is possible that the accumulation of the active Hck affects the structure of the Golgi and thereby perturbs the trafficking of Fms.…”

Section: Discussionmentioning

confidence: 99%

Interaction between Hck and HIV-1 Nef negatively regulates cell surface expression of M-CSF receptor

Hiyoshi¹,

Suzu²,

Yoshidomi³

et al. 2008

Blood

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Nef is a multifunctional pathogenetic protein of HIV-1, the interaction of which with Hck, a Src tyrosine kinase highly expressed in macrophages, has been shown to be responsible for the development of AIDS. However, how the Nef-Hck interaction leads to the functional aberration of macrophages is poorly understood. We recently showed that Nef markedly inhibited the activity of macrophage colonystimulating factor (M-CSF), a primary cytokine for macrophages. Here IntroductionHIV-1 infections lead to the development of AIDS by causing progressive degeneration of the immune system. [1][2][3] The main cellular targets of HIV-1 are CD4 ϩ T cells and macrophages, and the depletion of CD4 ϩ T cells caused by an infection is suggested to account for many aspects of the pathogenesis of HIV-1. [1][2][3] Meanwhile, a number of studies have revealed the functional aberration of HIV-1-infected macrophages. 4,5 Infected macrophages showed an altered profile of the production of cytokine/chemokines 4 or migratory capacity, 5 which might contribute to the uncontrolled homeostasis of the immune system. Indeed, functional analyses of HIV-1 Nef protein have revealed that macrophages as well as CD4 ϩ T cells play an important role in the development of AIDS.Nef is a 25-to 30-kDa protein with no enzymatic activity encoded by the HIV-1 genome. 6,7 Studies of HIV-1-infected patients have clearly demonstrated Nef to be a critical determinant of the development of AIDS: HIV-1 strains without an intact Nef gene were frequently isolated from nonprogressive long-term survivors. 8,9 Subsequent study of HIV-1 transgenic mice confirmed the pathogenetic activity of Nef: targeted expression of the entire coding sequence of HIV-1 in CD4 ϩ T cells and macrophages caused a severe AIDS-like disease in mice, which was completely abolished by the disruption of the Nef gene. 10 Importantly, only an amino acid substitution in the proline-rich (PxxP) motifs of Nef was sufficient to protect mice from the development of AIDS-like disease. 11 A number of studies have revealed that Nef interacts with a subset of cellular Src family tyrosine kinases, via the PxxP motifs. 12-15 The Nef PxxP motifs had an affinity for the Src homology (SH3) domain of Hck, Lyn, and possibly c-Src, but not of Fgr, Fyn, Lck, In particular, the interaction between the Nef PxxP motifs and the Hck SH3 domain was likely to be important, because the interaction caused the activation of Hck. [13][14][15] Indeed, a study with HIV-1 transgenic mice clearly demonstrated the importance of the Nef-Hck interaction for the development of AIDS: the appearance of the AIDS-like disease was significantly delayed when the HIV-1 transgenic mice expressing an intact Nef gene were crossed with an hck Ϫ/Ϫ background. 11 Given that Hck is expressed in macrophages but not in CD4 ϩ T cells, 16 the finding indicates that the Nef-Hck interaction in macrophages is at least in part responsible for the development of AIDS. However, little is known of the molecular mechanisms by which the Nef-Hck interaction c...

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“…Circularity values vary from 1 (for a perfect circle) to 0. Values below 1 indicate an elongated or stellate cell body and/or an increasing number of cellular processes (Berezin et al, 1997;Bard et al, 2003). For graphic presentation, normalized mean values ± s.e.m.…”

Section: Image Analysismentioning

confidence: 99%

Manipulation of redox signaling in mammalian cells enabled by controlled photogeneration of reactive oxygen species

Posen

Kalchenko

Seger

et al. 2005

Journal of Cell Science

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Reactive oxygen species (ROS) comprise a group of noxious byproducts of oxidative processes which participate in the induction of many common diseases. However, understanding their role in the regulation of normal physiological redox signaling is currently evolving. Detailed study of the dynamic functions of ROS within the biological milieu is difficult because of their high chemical reactivity, short lifetime, minute concentrations and cytotoxicity at high concentrations. In this study, we show that increasing intracellular ROS levels, set off by controlled in situ photogeneration of a nontoxic bacteriochlorophyll-based sensitizer initiate responses in cultured melanoma cells. Using hydroethidine as detector, we determined light-dependent generation of superoxide and hydroxyl radicals in cell-free and cell culture models. Monitoring the ROS-induced responses revealed individual and differential behavior of protein kinases [p38, mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and Akt] as well as effects on the subcellular distribution of phosphorylated p38. Furthermore, alterations in morphology and motility and effects on cell viability as a function of time and photosensitizer doses were observed. Following mild ROS challenge, enzymatic and cellular changes were observed in the majority of the cells, without inducing extensive cell death. However, upon vigorous ROS challenge, a similar profile of the overall responses was observed, terminating in cell death. This study shows that precisely controlled photogeneration of ROS can provide simple, fine-tuned, noninvasive manipulation of ROS-sensitive cellular responses ranging from individual enzymes to gross behavior of target cells. The observations made with this tool enable a dynamic and causal correlation, presenting a new alternative for studying the role of ROS in cellular redox signaling.

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Src Regulates Golgi Structure and KDEL Receptor-dependent Retrograde Transport to the Endoplasmic Reticulum

Cited by 99 publications

References 24 publications

Src kinase regulates the integrity and function of the Golgi apparatus via activation of dynamin 2

Src kinase regulates the integrity and function of the Golgi apparatus via activation of dynamin 2

Interaction between Hck and HIV-1 Nef negatively regulates cell surface expression of M-CSF receptor

Manipulation of redox signaling in mammalian cells enabled by controlled photogeneration of reactive oxygen species

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