Heat Shock Proteins Regulate Activation-induced Proteasomal Degradation of the Mature Phosphorylated Form of Protein Kinase C

Lum, Michelle A.; Balaburski, Gregor M.; Murphy, Maureen E.; Black, Adrian R.; Black, Jennifer D.

doi:10.1074/jbc.m112.437095

Cited by 19 publications

(30 citation statements)

References 89 publications

(76 reference statements)

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“…Detailed analysis of this organelle have revealed it to serve as an intracellular hub for the accumulation of internalized cell surface receptors prior to their redirection to other destinations such as recycling back to cell surface or targeting to the lysosome. Indeed, the down-regulation of PKC-␣ upon its sustained activation with bryostatin or PMA has also been linked to endosome-lysosome traffic (109) and this effect is enhanced by 17-AAG (110). Biochemical characterization of the pericentrion/ERC compartment revealed that it contains a number of cell surface receptors including EGFR (67).…”

Section: Discussionmentioning

confidence: 99%

A Kinase Inhibitor Screen Reveals Protein Kinase C-dependent Endocytic Recycling of ErbB2 in Breast Cancer Cells

Bailey

Luan

Tom

et al. 2014

Journal of Biological Chemistry

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ErbB2 overexpression drives oncogenesis in 20–30% cases of breast cancer. Oncogenic potential of ErbB2 is linked to inefficient endocytic traffic into lysosomes and preferential recycling. However, regulation of ErbB2 recycling is incompletely understood. We used a high-content immunofluorescence imaging-based kinase inhibitor screen on SKBR-3 breast cancer cells to identify kinases whose inhibition alters the clearance of cell surface ErbB2 induced by Hsp90 inhibitor 17-AAG. Less ErbB2 clearance was observed with broad-spectrum PKC inhibitor Ro 31-8220. A similar effect was observed with Go 6976, a selective inhibitor of classical Ca2+-dependent PKCs (α, β1, βII, and γ). PKC activation by PMA promoted surface ErbB2 clearance but without degradation, and ErbB2 was observed to move into a juxtanuclear compartment where it colocalized with PKC-α and PKC-δ together with the endocytic recycling regulator Arf6. PKC-α knockdown impaired the juxtanuclear localization of ErbB2. ErbB2 transit to the recycling compartment was also impaired upon PKC-δ knockdown. PMA-induced Erk phosphorylation was reduced by ErbB2 inhibitor lapatinib, as well as by knockdown of PKC-δ but not that of PKC-α. Our results suggest that activation of PKC-α and -δ mediates a novel positive feedback loop by promoting ErbB2 entry into the endocytic recycling compartment, consistent with reported positive roles for these PKCs in ErbB2-mediated tumorigenesis. As the endocytic recycling compartment/pericentrion has emerged as a PKC-dependent signaling hub for G-protein-coupled receptors, our findings raise the possibility that oncogenesis by ErbB2 involves previously unexplored PKC-dependent endosomal signaling.

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Section: Discussionmentioning

confidence: 99%

A Kinase Inhibitor Screen Reveals Protein Kinase C-dependent Endocytic Recycling of ErbB2 in Breast Cancer Cells

Bailey

Luan

Tom

et al. 2014

Journal of Biological Chemistry

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“…Chronic DiC 8 Stimulation Does Not Result in Down-regulation of PKC␣-The ability of DiC 8 to support sustained activation of PKC␣ was surprising because it is well established that prolonged stimulation of PKC isozymes can lead to long term desensitization via degradation of the activated kinase (19,21,22). This down-regulation can be readily seen in PMA-and bryostatin-treated IEC-18 cells: as shown in Fig.…”

Section: Activation and Reversementioning

confidence: 84%

“…Two mechanisms have been described for agonist-induced ubiquitination/proteasomal degradation of PKC␣ (19,21,23). One pathway involves activation-dependent priming site dephosphorylation, which both inactivates the kinase and targets it for ubiquitin-dependent proteasomal degradation (9,19).…”

Section: Activation and Reversementioning

confidence: 99%

“…This finding pointed to an inability of DiC 8 to promote degradation of the enzyme. Ago- nist-induced down-regulation of PKC␣ can involve ubiquitination of the enzyme and degradation by the proteasome or lipid raft-dependent intracellular trafficking and lysosomal processing (19,21,22). Involvement of lysosomal degradation can be excluded because repeated addition of DiC 8 does not induce internalization of the protein (Fig.…”

Section: Activation and Reversementioning

confidence: 99%

“…Another mechanism of inactivation, engaged in response to long term stimulation by physiological activators or pharmacological agonists, is agonist-induced degradation of PKCs. For PKC␣, these long term desensitization mechanisms, which appear to be triggered in a cell type-and agonist-specific manner, include (a) dephosphorylation of activation loop (Thr 497 ), turn motif (Thr 638 ), and hydrophobic motif (Ser 657 ) priming sites followed by proteasomal processing of the dephosphorylated species, (b) ubiquitin/proteasome-dependentdegradationofthemature,fullyphosphorylated enzyme at the plasma membrane, and (c) vesicle trafficking-dependent degradation in lysosomes (19,(21)(22)(23). Agonist-induced degradation of PKCs leads to loss of associated signaling and reversal of their downstream effects in the continued presence of agonists.…”

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confidence: 99%

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Protein Kinase Cα (PKCα) Is Resistant to Long Term Desensitization/Down-regulation by Prolonged Diacylglycerol Stimulation

Lum¹,

Barger

Hsu

et al. 2016

Journal of Biological Chemistry

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Sustained activation of PKC␣ is required for long term physiological responses, such as growth arrest and differentiation. However, studies with pharmacological agonists (e.g. phorbol 12-myristate 13-acetate (PMA)) indicate that prolonged stimulation leads to PKC␣ desensitization via dephosphorylation and/or degradation. The current study analyzed effects of chronic stimulation with the physiological agonist diacylglycerol. Repeated addition of 1,2-dioctanoyl-sn-glycerol (DiC 8 ) resulted in sustained plasma membrane association of PKC␣ in a pattern comparable with that induced by PMA. However, although PMA potently down-regulated PKC␣, prolonged activation by DiC 8 failed to engage known desensitization mechanisms, with the enzyme remaining membrane-associated and able to support sustained downstream signaling. DiC 8 -activated PKC␣ did not undergo dephosphorylation, ubiquitination, or internalization, early events in PKC␣ desensitization. Although DiC 8 efficiently down-regulated novel PKCs PKC␦ and PKC⑀, differences in Ca 2؉ sensitivity and diacylglycerol affinity were excluded as mediators of the selective resistance of PKC␣. Roles for Hsp/Hsc70 and Hsp90 were also excluded. PMA, but not DiC 8 , targeted PKC␣ to detergent-resistant membranes, and disruption of these domains with cholesterol-binding agents demonstrated a role for differential membrane compartmentalization in selective agonist-induced degradation. Chronic DiC 8 treatment failed to desensitize PKC␣ in several cell types and did not affect PKC␤I; thus, conventional PKCs appear generally insensitive to desensitization by sustained diacylglycerol stimulation. Consistent with this conclusion, prolonged (several-day) membrane association/activation of PKC␣ is seen in self-renewing epithelium of the intestine, cervix, and skin. PKC␣ deficiency affects gene expression, differentiation, and tumorigenesis in these tissues, highlighting the importance of mechanisms that protect PKC␣ from desensitization in vivo.

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Role of Heat Shock Protein 90 in Regulating Downstream Signal Transduction Cascades

Duron

Stine

et al. 2019

Heat Shock Proteins

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Heat Shock Proteins Regulate Activation-induced Proteasomal Degradation of the Mature Phosphorylated Form of Protein Kinase C

Cited by 19 publications

References 89 publications

A Kinase Inhibitor Screen Reveals Protein Kinase C-dependent Endocytic Recycling of ErbB2 in Breast Cancer Cells

A Kinase Inhibitor Screen Reveals Protein Kinase C-dependent Endocytic Recycling of ErbB2 in Breast Cancer Cells

Protein Kinase Cα (PKCα) Is Resistant to Long Term Desensitization/Down-regulation by Prolonged Diacylglycerol Stimulation

Role of Heat Shock Protein 90 in Regulating Downstream Signal Transduction Cascades

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