RNAi screen identifies KIF15 as a novel regulator of integrin endocytic trafficking

Eskova, Anastasia; Knapp, Bettina L.; Matelska, Dorota; Reusing, Susanne; Arjonen, Antti; Lisauskas, Tautvydas; Pepperkok, Rainer; Russell, Robert B.; Eils, Roland; Ivaska, Johanna; Kaderali, Lars; Erfle, Holger; Starkuviene, Vytaute

doi:10.1242/jcs.137281

Cited by 26 publications

(24 citation statements)

References 141 publications

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“…Drechsler et al reported that KIF15 is a second tetrameric spindle motor (in addition to kinesin-5, Eg5) and reported the mechanisms by which hKIF15 and its inhibitor hTpx2 modulate spindle microtubule architecture (Tanenbaum et al , 2009; Drechsler et al , 2014; Eskova et al , 2014). The motor domain structure of KIF15 was captured in the ‘ATP-like’ configuration, with the neck linker docked onto the catalytic core.…”

Section: Discussionmentioning

confidence: 99%

KIF15 promotes pancreatic cancer proliferation via the MEK–ERK signalling pathway

et al. 2017

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Background:Pancreatic cancer is highly malignant and characterised by rapid and uncontrolled growth. While some of the important regulatory networks involved in pancreatic cancer have been determined, the cancer relevant genes have not been fully identified.Methods:We screened genes that may control proliferation in pancreatic cancer in seven pairs of matched pancreatic cancer and normal pancreatic tissue samples. We examined KIF15 expression in pancreatic cancer tissues and the effect of KIF15 on cell proliferation in vitro and in vivo. The mechanisms underlying KIF15 promotion of cell proliferation were investigated.Results:mRNA microarray and functional analysis identified 22 genes that potentially play an important role in the proliferation of pancreatic cancer. High-content siRNA screening evaluated whether silencing these 22 genes affected proliferation of pancreatic cancer. Notably, silencing KIF15 exhibited the most potent inhibition of proliferation compared with the rest of the 22 genes. KIF15 was upregulated in human pancreatic cancer tissues, and higher KIF15 expression levels correlated with shorter patient survival times. Upregulation KIF15 promoted pancreatic cancer growth. KIF15 upregulated cyclin D1, CDK2, and phospho-RB and also promoted G1/S transition in pancreatic cancer cells. KIF15 upregulation activated MEK–ERK signalling by increasing p-MEK and p-ERK levels. MEK–ERK inhibitors successfully inhibited cell cycle progression, and PD98059 blocked KIF15-mediated pancreatic cancer proliferation in vivo and in vitro.Conclusions:This study identified KIF15 as a critical regulator that promotes pancreatic cancer proliferation, broadening our understanding of KIF15 function in tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

KIF15 promotes pancreatic cancer proliferation via the MEK–ERK signalling pathway

et al. 2017

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“…In contrast, tail retraction leads to loss of cell polarity and re-establishment of a new cell axis (Theisen et al, 2012). KIF15, another kinesin motor, was recently identified in a fluorescence-microscopy-based RNA interference screen as a new regulator of inactive α2β1 integrin traffic (Eskova et al, 2014). However, unlike KIF1C, KIF15 promotes α2β1 integrin endocytosis through the transport of Dab2 to the plasma membrane to engage the α2 integrin tail (Fig.…”

Section: The Cell Cytoskeleton and Integrin Trafficmentioning

confidence: 99%

Integrin traffic – the update

Franceschi

Hamidi

Alanko

et al. 2015

Journal of Cell Science

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263

274

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Integrins are a family of transmembrane cell surface molecules that constitute the principal adhesion receptors for the extracellular matrix (ECM) and are indispensable for the existence of multicellular organisms. In vertebrates, 24 different integrin heterodimers exist with differing substrate specificity and tissue expression. Integrin–extracellular-ligand interaction provides a physical anchor for the cell and triggers a vast array of intracellular signalling events that determine cell fate. Dynamic remodelling of adhesions, through rapid endocytic and exocytic trafficking of integrin receptors, is an important mechanism employed by cells to regulate integrin–ECM interactions, and thus cellular signalling, during processes such as cell migration, invasion and cytokinesis. The initial concept of integrin traffic as a means to translocate adhesion receptors within the cell has now been expanded with the growing appreciation that traffic is intimately linked to the cell signalling apparatus. Furthermore, endosomal pathways are emerging as crucial regulators of integrin stability and expression in cells. Thus, integrin traffic is relevant in a number of pathological conditions, especially in cancer. Nearly a decade ago we wrote a Commentary in Journal of Cell Science entitled ‘Integrin traffic’. With the advances in the field, we felt it would be appropriate to provide the growing number of researchers interested in integrin traffic with an update.

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“…Another microtubule-dependent motor protein which was recently identified in a screen for regulators of a2 integrin endocytosis is the kinesin KIF15 [80]. Depletion of KIF15 inhibited the intracellular accumulation of a2 integrin, which is likely due to the fact that it also induced a loss of plasma membrane-associated Dab2, as Dab2 depletion mimicked KIF15 depletion [80].…”

Section: Integrin Traffickingmentioning

confidence: 99%

On the move: endocytic trafficking in cell migration

Maritzen

Schachtner

Legler

2015

Cell. Mol. Life Sci.

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Directed cell migration is a fundamental process underlying diverse physiological and pathophysiological phenomena ranging from wound healing and induction of immune responses to cancer metastasis. Recent advances reveal that endocytic trafficking contributes to cell migration in multiple ways. (1) At the level of chemokines and chemokine receptors: internalization of chemokines by scavenger receptors is essential for shaping chemotactic gradients in tissue, whereas endocytosis of chemokine receptors and their subsequent recycling is key for maintaining a high responsiveness of migrating cells. (2) At the level of integrin trafficking and focal adhesion dynamics: endosomal pathways do not only modulate adhesion by delivering integrins to their site of action, but also by supplying factors for focal adhesion disassembly. (3) At the level of extracellular matrix reorganization: endosomal transport contributes to tumor cell migration not only by targeting integrins to invadosomes but also by delivering membrane type 1 matrix metalloprotease to the leading edge facilitating proteolysis-dependent chemotaxis. Consequently, numerous endocytic and endosomal factors have been shown to modulate cell migration. In fact key modulators of endocytic trafficking turn out to be also key regulators of cell migration. This review will highlight the recent progress in unraveling the contribution of cellular trafficking pathways to cell migration.

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RNAi screen identifies KIF15 as a novel regulator of integrin endocytic trafficking

Cited by 26 publications

References 141 publications

KIF15 promotes pancreatic cancer proliferation via the MEK–ERK signalling pathway

KIF15 promotes pancreatic cancer proliferation via the MEK–ERK signalling pathway

Integrin traffic – the update

On the move: endocytic trafficking in cell migration

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