Phosphorylation of Rab-coupling protein by LMTK3 controls Rab14-dependent EphA2 trafficking to promote cell:cell repulsion

Gundry, Christine; Marco, Sergi; Rainero, Elena; Miller, Bryan W.; Dornier, Emmanuel; Mitchell, Louise; Caswell, Patrick T.; Campbell, Andrew D.; Hogeweg, Anna; Sansom, Owen J.; Morton, Jennifer P.; Norman, Jim C.

doi:10.1038/ncomms14646

Cited by 43 publications

(52 citation statements)

References 40 publications

(50 reference statements)

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“…Notably, FHOD3 knockdown does not impact on migration on 2D surfaces, but suppresses filopodial‐driven invasion in cell‐derived 3D matrix and 3D hydrogels . EphA2 is also a cargo of RCP, in this case directed by Rab14, and this trafficking pathway controls invasion and metastasis in pancreatic cancer (Figure ). Additionally, hepatocyte growth factor (HGF) stimulation leads to co‐internalization of c‐Met (HFGR) and β1 integrin, and is required for downstream signalling in a variety of cell types, and indeed c‐Met can follow a RCP‐α5β1 recycling route to promote cancer cell invasion (Figure ).…”

Section: Rtk Trafficking and Signalling In Cell Migrationmentioning

confidence: 99%

Vesicle trafficking pathways that direct cell migration in 3D matrices and in vivo

Wilson

Allen

Caswell

2018

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Cell migration is a vital process in development and disease, and while the mechanisms that control motility are relatively well understood on two‐dimensional surfaces, the control of cell migration in three dimensions (3D) and in vivo has only recently begun to be understood. Vesicle trafficking pathways have emerged as a key regulatory element in migration and invasion, with the endocytosis and recycling of cell surface cargos, including growth factor and chemokine receptors, adhesion receptors and membrane‐associated proteases, being of major importance. We highlight recent advances in our understanding of how endocytic trafficking controls the availability and local activity of these cargoes to influence the movement of cells in 3D matrix and in developing organisms. In particular, we discuss how endocytic trafficking of different receptor classes spatially restricts signals and activity, usually to the leading edge of invasive cells.

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Section: Rtk Trafficking and Signalling In Cell Migrationmentioning

confidence: 99%

Vesicle trafficking pathways that direct cell migration in 3D matrices and in vivo

Wilson

Allen

Caswell

2018

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“…52) They showed that EphA2 was constitutively internal- ized and returned to the cell membrane rapidly. However, upon hepatocyte growth factor (HGF) stimulation, the AktEphA2 pathway as well as the LMTK3-RCP pathway was activated.…”

Section: Cell Motility and Cell Morphologymentioning

confidence: 99%

“…Both the LMTK3-RCP signaling pathway and Akt-EphA2 signaling pathway were necessary for efficient invasion and metastasis in an in vivo model of pancreatic cancer. 52) It is well known that the Rho family of small GTPases plays critical roles in the regulation of cell motility and morphology. [53][54][55] Kawai et al 56) demonstrated that the interaction of EphA2 and Ephexin4, which is one of the RhoG guanine nucleotide exchanges, was induced in an EphA2 Ser-897 phosphorylation-dependent manner.…”

Section: Cell Motility and Cell Morphologymentioning

confidence: 99%

Emerging and Diverse Functions of the EphA2 Noncanonical Pathway in Cancer Progression

Zhou

Sakurai

2017

Biological & Pharmaceutical Bulletin

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Erythropoietin-producing hepatocellular receptor A2 (EphA2) receptor tyrosine kinase controls multiple physiological processes to maintain homeostasis in normal cells. In many types of solid tumors, it has been reported that EphA2 is overexpressed and plays a critical role in oncogenic signaling. However, in recent years, the opposing functions of EphA2 have been explained by the canonical and noncanonical signaling pathways. Ligand-and tyrosine kinase-dependent EphA2 activation (the canonical pathway) inhibits cancer cell proliferation and motility. In contrast, ligand-and tyrosine kinase-independent EphA2 signaling (the noncanonical pathway) promotes tumor survival and metastasis and controls acquired drug resistance and maintenance of cancer stem cell-like properties. Evidence has accumulated showing that the EphA2 noncanonical pathway is mainly regulated by inflammatory cytokines and growth factors via phosphorylation at Ser-897 in the intracellular C-tail region via some serine/threonine kinases, including p90 ribosomal S6 kinase. In this review, we focus on the regulation of Ser-897 phosphorylation and its functional importance in tumor malignancy and discuss future therapeutic targeting.

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“…What drives formation of Rab14/MACF2/CAMSAP3 complex during telophase, but blocks it from functioning in metaphase and anaphase? Interesting, Rab14 was also implicated in regulating epithelial cell polarity (Lu and Wilson 2016), as well as recycling of integrins during cell migration (Gundry et al, 2017). Both of these cellular processes are also dependent on actin and microtubule dynamics, thus, it will be interesting to see whether Rab14 interaction with MACF2/CAMSAP3 complex may have functions during cell polarization and migration.…”

Section: Discussionmentioning

confidence: 99%

Rab14/MACF2/CAMSAP3 Complex Regulates Endosomal Targeting to the Abscission Site During Cytokinesis

Prekeris

Gibieža

Peterman

et al. 2020

Preprint

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Abscission is complex cellular process that is required for mitotic division. It is well-established that coordinated and localized changes in actin and microtubule dynamics are vital for cytokinetic ring formation, as well as establishment of the abscission site. Actin cytoskeleton reorganization during abscission would not be possible without the interplay between Rab11-and Rab35containing endosomes and their effector proteins, whose roles in regulating endocytic pathways at the cleavage furrow have now been studied extensively. Here, we identified Rab14 as novel regulator of abscission. We demonstrate that depletion of Rab14 causes either cytokinesis failure or significantly prolongs division time. We show that Rab14 regulates the efficiency of recruiting Rab11-endosomes to the central spindle microtubules and that Rab14 knockout leads to inhibition of actin clearance at the abscission site. Finally, we demonstrate that Rab14 binds to microtubule minus-end interacting MACF2/CAMSAP3 complex and that this binding is required for targeting of early endosomes to the central spindle. Collectively, our data identified Rab14/MACF2/CAMSAP3 as a protein complex that regulates Rab11-endosome targeting and the establishment of the abscission site.

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Phosphorylation of Rab-coupling protein by LMTK3 controls Rab14-dependent EphA2 trafficking to promote cell:cell repulsion

Cited by 43 publications

References 40 publications

Vesicle trafficking pathways that direct cell migration in 3D matrices and in vivo

Vesicle trafficking pathways that direct cell migration in 3D matrices and in vivo

Emerging and Diverse Functions of the EphA2 Noncanonical Pathway in Cancer Progression

Rab14/MACF2/CAMSAP3 Complex Regulates Endosomal Targeting to the Abscission Site During Cytokinesis

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