Palmitoylation regulates the intracellular trafficking and stability of c-Met

Coleman, David T.; Gray, Alana L.; Kridel, Steven J.; Cardelli, James A.

doi:10.18632/oncotarget.8706

Cited by 34 publications

(27 citation statements)

References 64 publications

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“…This requires palmitoylation of its cysteine residues for migration to the lipid rafts, where it can activate the TBK1-IRF3 pathway [51]. MET tyrosine kinase is activated and palmitoylated on its extracellular domain at the Golgi [69, 70], and lipid rafts contribute to receptor distribution and stability [70, 71]. These studies raise the interesting possibility that incorporation of KIT into the lipid rafts of the Golgi is involved in protein acylation.…”

Section: Discussionmentioning

confidence: 99%

N822K- or V560G-mutated KIT activation preferentially occurs in lipid rafts of the Golgi apparatus in leukemia cells

Obata¹,

Hara²,

Shiina³

et al. 2019

Cell Commun Signal

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Background KIT tyrosine kinase is expressed in mast cells, interstitial cells of Cajal, and hematopoietic cells. Permanently active KIT mutations lead these host cells to tumorigenesis, and to such diseases as mast cell leukemia (MCL), gastrointestinal stromal tumor (GIST), and acute myeloid leukemia (AML). Recently, we reported that in MCL, KIT with mutations ( D816V , human; D814Y , mouse) traffics to endolysosomes (EL), where it can then initiate oncogenic signaling. On the other hand, KIT mutants including KIT D814Y in GIST accumulate on the Golgi, and from there, activate downstream. KIT mutations, such as N822K , have been found in 30% of core binding factor-AML (CBF-AML) patients. However, how the mutants are tyrosine-phosphorylated and where they activate downstream molecules remain unknown. Moreover, it is unclear whether a KIT mutant other than KIT D816V in MCL is able to signal on EL. Methods We used leukemia cell lines, such as Kasumi-1 ( KIT N822K , AML), SKNO-1 ( KIT N822K , AML), and HMC-1.1 ( KIT V560G , MCL), to explore how KIT transduces signals in these cells and to examine the signal platform for the mutants using immunofluorescence microscopy and inhibition of intracellular trafficking. Results In AML cell lines, KIT N822K aberrantly localizes to EL. After biosynthesis, KIT traffics to the cell surface via the Golgi and immediately migrates to EL through endocytosis in a manner dependent on its kinase activity. However, results of phosphorylation imaging show that KIT is preferentially activated on the Golgi. Indeed, blockade of KIT N822K migration to the Golgi with BFA/M-COPA inhibits the activation of KIT downstream molecules, such as AKT, ERK, and STAT5, indicating that KIT signaling occurs on the Golgi. Moreover, lipid rafts in the Golgi play a role in KIT signaling. Interestingly, KIT V560G in HMC-1.1 migrates and activates downstream in a similar manner to KIT N822K in Kasumi-1. Conclusions In AML, KIT N822K mislocalizes to EL. Our findings, however, suggest that the mutant transduces phosphorylation signals on lipid rafts of the Golgi in leukemia cells. Unexpectedly, the KIT V560G signal platform in MCL is similar to that of KIT N822K in AML. These observations provide new insights into the pathogenic role of KIT mutants as well as that of other mutant molecules. Electronic supplementary material The online version of this article (10.1186/s12964-01...

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Section: Discussionmentioning

confidence: 99%

N822K- or V560G-mutated KIT activation preferentially occurs in lipid rafts of the Golgi apparatus in leukemia cells

Obata¹,

Hara²,

Shiina³

et al. 2019

Cell Commun Signal

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“…In fact, other studies have reported that integrin ␣3␤1 and the tetraspanin family can interact with type II of PI4K (25)(26)(27). In addition, palmitoylation could also be a plausible factor because PI4Ks are proteins with membrane association and activity that are highly dependent on such a modification (68,69), and palmitoylation also plays an important role in the association between integrin and several molecules, such as tetraspanin and c-Met (70,71). We assume that the association between PI4KII␣ and ␣3, but ␣5, might also relate to tetraspanin or palmitoylation.…”

Section: Importance Of the Pi4k-integrin ␣3␤1 Complex For Sialylationmentioning

confidence: 99%

A complex between phosphatidylinositol 4-kinase IIα and integrin α3β1 is required for N-glycan sialylation in cancer cells

Isaji

Kameyama

et al. 2019

Journal of Biological Chemistry

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Aberrant N-glycan sialylation of glycoproteins is closely associated with malignant phenotypes of cancer cells and metastatic potential, which includes cell adhesion, migration, and growth. Recently, phosphatidylinositol 4-kinase II␣ (PI4KII␣), which is localized to the trans-Golgi network, was identified as a regulator of Golgi phosphoprotein 3 (GOLPH3) and of vesicle transport in the Golgi apparatus. GOLPH3 is a target of PI4KII␣ and helps anchor sialyltransferases and thereby regulates sialylation of cell surface receptors. However, how PI4KII␣-mediated sialyation of cell surface proteins is regulated remains unclear. In this study, using several cell lines, CRISPR/Cas9-based gene knockout and short hairpin RNA-mediated silencing, RT-PCR, lentivirus-mediated overexpression, and immunoblotting methods, we confirmed that PI4KII␣ knockdown suppresses the sialylation of N-glycans on the cell surface, in Akt phosphorylation and activation, and integrin ␣3-mediated cell migration of MDA-MB-231 breast cancer cells. Interestingly, both integrin ␣3␤1 and PI4KII␣ co-localized to the trans-Golgi network, where they physically interacted with each other, and PI4KII␣ specifically associated with integrin ␣3 but not ␣5. Furthermore, overexpression of both integrin ␣3␤1 and PI4KII␣ induced hypersialylation. Conversely, integrin ␣3 knockout significantly inhibited the sialylation of membrane proteins, such as the epidermal growth factor receptor, as well as in total cell lysates. These findings suggest that the malignant phenotype of cancer cells is affected by a sialylation mechanism that is regulated by a complex between PI4KII␣ and integrin ␣3␤1.

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“…transferrin receptor, c-Met, LRP6, TEM8, EGF receptor), proteins involved in synaptic signaling (e.g. PSD-95, AMPA receptor), among others (Chamberlain and Shipston 2015;Coleman et al 2016;Fukata et al 2016;Collins et al 2017;Howie et al 2018).…”

Section: Introductionmentioning

confidence: 99%

The molecular era of protein S-acylation: spotlight on structure, mechanisms, and dynamics

Zaballa

Goot

2018

Critical Reviews in Biochemistry and Molecular Biology

102

129

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S-Acylation (commonly referred to as S-palmitoylation) is a post-translational modification consisting in the covalent attachment of an acyl chain to a cysteine residue of the target protein. The lability of the resulting thioester bond gives S-acylation an essential characteristic: its reversibility. S-acylation dynamically regulates different aspects in the life of a protein (including stability, localization, interactome, and function) and, thus, plays critical roles in cellular physiology. For long, the reversibility of S-acylation has been neglected and thereby its potential as a regulatory mechanism for protein function undervalued. Thanks to technological advances, the field has now entered its golden era. A great diversity of interesting targets is being identified, the physio-pathological importance of the modification is starting to be revealed, structural information on the enzymes is becoming available, and the regulatory dynamics are gradually being understood. Here we will review the most recent literature in the S-acylation field, with a special focus on the molecular aspects of the modification, its regulation, and its consequences.

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Palmitoylation regulates the intracellular trafficking and stability of c-Met

Cited by 34 publications

References 64 publications

N822K- or V560G-mutated KIT activation preferentially occurs in lipid rafts of the Golgi apparatus in leukemia cells

N822K- or V560G-mutated KIT activation preferentially occurs in lipid rafts of the Golgi apparatus in leukemia cells

A complex between phosphatidylinositol 4-kinase IIα and integrin α3β1 is required for N-glycan sialylation in cancer cells

The molecular era of protein S-acylation: spotlight on structure, mechanisms, and dynamics

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