Phase-separated foci of EML4-ALK facilitate signalling and depend upon an active kinase conformation

ABSTRACT: Variants of the oncogenic EML4-ALK fusion protein contain a similar region of ALK encompassing the kinase domain, but different portions of EML4. Here we show that EML4-ALK V1 and V3 proteins form cytoplasmic foci that contain components of the MAPK, PLC and PI3K signalling pathways. The ALK inhibitors ceritinib and lorlatinib dissolve these foci and EML4-ALK V3 but not V1 protein re-localises to microtubules, an effect recapitulated in a catalytically-inactive EML4-ALK mutant. Mutations that promote a constitutively active ALK stabilise the cytoplasmic foci even in the presence of these inhibitors. In contrast, the inhibitor alectinib increases foci formation of both wild-type and catalytically-inactive EML4-ALK V3 proteins, but not a Lys-Glu salt-bridge mutant. We propose that EML4-ALK

SUBMITTER: Josephina Sampson 

PROVIDER: S-SCDT-EMBOR-2021-53693V1 | biostudies-other |

REPOSITORIES: biostudies-other