NEK7 phosphorylation of cortactin modulates the migratory capacity of cells expressing EML4-ALK V3

Emily L. Richardson; Axel Knebel; Kees R. Straatman; Robert Gourlay; Douglas Lamont; Tara Hardy; Robert E. Turnbull; Susan W. Robinson; Laura O’Regan; Richard Bayliss; Andrew M. Fry

doi:10.1038/s41598-026-36484-4

NEK7 phosphorylation of cortactin modulates the migratory capacity of cells expressing EML4-ALK V3

Emily L. Richardson (Lead / Corresponding author)
, Axel Knebel
, Kees R. Straatman
, Robert Gourlay
, Douglas Lamont
, Tara Hardy
, Robert E. Turnbull
, Susan W. Robinson
, Laura O’Regan
, Richard Bayliss (Lead / Corresponding author)
, Andrew M. Fry

MRC PPU

Research output: Contribution to journal › Article › peer-review

Abstract

EML4-ALK is a common oncogenic driver of non-small cell lung cancer. Distinct EML4-ALK variants cause different rates of disease progression, with patients expressing variant 3 (V3) exhibiting accelerated metastasis. Cells expressing EML4-ALK V3 develop a mesenchymal-like morphology and enhanced migration that is dependent on the NEK9 and NEK7 kinases. However, downstream substrates of these kinases relevant to these phenotypes are largely unknown. Here, we show that the actin-binding protein cortactin is phosphorylated by NEK7 within the F-actin-binding region (ABR) and that depletion of cortactin abrogates the morphological and migration phenotypes induced by EML4-ALK V3. Expression of constitutively active mutants of NEK9 or NEK7 causes similar cortactin-dependent morphological and migration changes. Cortactin co-localises with NEK7 and EML4-ALK V3 at branched filopodia-like extensions that are also generated upon expression of a cortactin protein with phospho-mimetic mutations in the ABR. In contrast, phospho-null mutations dissociate cortactin from F-actin. We propose that EML4-ALK V3 alters cell morphology and promotes directed cell migration by modulating the actin cytoskeleton via NEK7-mediated phosphorylation of cortactin within its ABR.

Original language	English
Article number	6407
Journal	Scientific Reports
Volume	16
Issue number	1
Early online date	27 Jan 2026
DOIs	https://doi.org/10.1038/s41598-026-36484-4
Publication status	Published - 16 Feb 2026

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Actin
Cell migration
Cortactin
EML4-ALK
NEK7
NEK9

ASJC Scopus subject areas

General

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title = "NEK7 phosphorylation of cortactin modulates the migratory capacity of cells expressing EML4-ALK V3",

abstract = "EML4-ALK is a common oncogenic driver of non-small cell lung cancer. Distinct EML4-ALK variants cause different rates of disease progression, with patients expressing variant 3 (V3) exhibiting accelerated metastasis. Cells expressing EML4-ALK V3 develop a mesenchymal-like morphology and enhanced migration that is dependent on the NEK9 and NEK7 kinases. However, downstream substrates of these kinases relevant to these phenotypes are largely unknown. Here, we show that the actin-binding protein cortactin is phosphorylated by NEK7 within the F-actin-binding region (ABR) and that depletion of cortactin abrogates the morphological and migration phenotypes induced by EML4-ALK V3. Expression of constitutively active mutants of NEK9 or NEK7 causes similar cortactin-dependent morphological and migration changes. Cortactin co-localises with NEK7 and EML4-ALK V3 at branched filopodia-like extensions that are also generated upon expression of a cortactin protein with phospho-mimetic mutations in the ABR. In contrast, phospho-null mutations dissociate cortactin from F-actin. We propose that EML4-ALK V3 alters cell morphology and promotes directed cell migration by modulating the actin cytoskeleton via NEK7-mediated phosphorylation of cortactin within its ABR.",

keywords = "Actin, Cell migration, Cortactin, EML4-ALK, NEK7, NEK9",

author = "Richardson, \{Emily L.\} and Axel Knebel and Straatman, \{Kees R.\} and Robert Gourlay and Douglas Lamont and Tara Hardy and Turnbull, \{Robert E.\} and Robinson, \{Susan W.\} and Laura O{\textquoteright}Regan and Richard Bayliss and Fry, \{Andrew M.\}",

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AU - Richardson, Emily L.

AU - Knebel, Axel

AU - Straatman, Kees R.

AU - Gourlay, Robert

AU - Lamont, Douglas

AU - Hardy, Tara

AU - Turnbull, Robert E.

AU - Robinson, Susan W.

AU - O’Regan, Laura

AU - Bayliss, Richard

AU - Fry, Andrew M.

PY - 2026/2/16

Y1 - 2026/2/16

N2 - EML4-ALK is a common oncogenic driver of non-small cell lung cancer. Distinct EML4-ALK variants cause different rates of disease progression, with patients expressing variant 3 (V3) exhibiting accelerated metastasis. Cells expressing EML4-ALK V3 develop a mesenchymal-like morphology and enhanced migration that is dependent on the NEK9 and NEK7 kinases. However, downstream substrates of these kinases relevant to these phenotypes are largely unknown. Here, we show that the actin-binding protein cortactin is phosphorylated by NEK7 within the F-actin-binding region (ABR) and that depletion of cortactin abrogates the morphological and migration phenotypes induced by EML4-ALK V3. Expression of constitutively active mutants of NEK9 or NEK7 causes similar cortactin-dependent morphological and migration changes. Cortactin co-localises with NEK7 and EML4-ALK V3 at branched filopodia-like extensions that are also generated upon expression of a cortactin protein with phospho-mimetic mutations in the ABR. In contrast, phospho-null mutations dissociate cortactin from F-actin. We propose that EML4-ALK V3 alters cell morphology and promotes directed cell migration by modulating the actin cytoskeleton via NEK7-mediated phosphorylation of cortactin within its ABR.

AB - EML4-ALK is a common oncogenic driver of non-small cell lung cancer. Distinct EML4-ALK variants cause different rates of disease progression, with patients expressing variant 3 (V3) exhibiting accelerated metastasis. Cells expressing EML4-ALK V3 develop a mesenchymal-like morphology and enhanced migration that is dependent on the NEK9 and NEK7 kinases. However, downstream substrates of these kinases relevant to these phenotypes are largely unknown. Here, we show that the actin-binding protein cortactin is phosphorylated by NEK7 within the F-actin-binding region (ABR) and that depletion of cortactin abrogates the morphological and migration phenotypes induced by EML4-ALK V3. Expression of constitutively active mutants of NEK9 or NEK7 causes similar cortactin-dependent morphological and migration changes. Cortactin co-localises with NEK7 and EML4-ALK V3 at branched filopodia-like extensions that are also generated upon expression of a cortactin protein with phospho-mimetic mutations in the ABR. In contrast, phospho-null mutations dissociate cortactin from F-actin. We propose that EML4-ALK V3 alters cell morphology and promotes directed cell migration by modulating the actin cytoskeleton via NEK7-mediated phosphorylation of cortactin within its ABR.

KW - Actin

KW - Cell migration

KW - Cortactin

KW - EML4-ALK

KW - NEK7

KW - NEK9

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NEK7 phosphorylation of cortactin modulates the migratory capacity of cells expressing EML4-ALK V3

Abstract

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Keywords

ASJC Scopus subject areas

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