Authors:	Mooz, Juliane Riegel, Kristina Ps, Hari Sadanandam, Anguraj Marini, Federico Klein, Matthias Werner, Ulrike Roth, Wilfried Wilken-Schmitz, Annett Tegeder, Irmgard Rajalingam, Krishnaraj
Title:	ARAF suppresses ERBB3 expression and metastasis in a subset of lung cancers
Online publication date:	25-Jan-2023
Year of first publication:	2022
Language:	english
Abstract:	RAF kinases are highly conserved serine/threonine kinases, and among the three RAF isoforms (ARAF, BRAF, and CRAF), the pathophysiological relevance of ARAF is not well defined. Here, we show that patients with lung cancer exhibit low expression of ARAF, which is associated with lymph node metastasis and poor patient survival. We uncover that depletion of ARAF promotes anchorage-independent growth and metastasis through activation of AKT signaling in a subset of lung cancer cells. We identified that loss of ARAF was associated with an increase in ERBB3 expression in a kinase-independent manner. ARAF suppressed the promoter activity of ERBB3, and reconstitution of ARAF in ARAF-depleted cells led to the reversal of enhanced ERBB3-AKT signaling. Furthermore, ARAF inhibited neuregulin 1 (hNRG1)–mediated AKT activation through controlling ERBB3 expression via the transcription factor KLF5. Our results disclose a critical dual role for ARAF kinase in the negative regulation of ERBB3-AKT signaling, thereby suppressing tumor metastasis.
DDC:	610 Medizin 610 Medical sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 04 Medizin
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-8645
Version:	Published version
Publication type:	Zeitschriftenaufsatz
Document type specification:	Scientific article
License:	CC BY-NC
Information on rights of use:	https://creativecommons.org/licenses/by-nc/4.0/
Journal:	Science advances 8 11
Pages or article number:	eabk1538
Publisher:	Assoc.
Publisher place:	Washington, DC u.a.
Issue date:	2022
ISSN:	2375-2548
Publisher DOI:	10.1126/sciadv.abk1538
Appears in collections:	DFG-491381577-G