ARAF suppresses ERBB3 expression and metastasis in a subset of lung cancers.
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ICR Authors
Authors
Mooz, J
Riegel, K
Ps, H
Sadanandam, A
Marini, F
Klein, M
Werner, U
Roth, W
Wilken-Schmitz, A
Tegeder, I
Rajalingam, K
Riegel, K
Ps, H
Sadanandam, A
Marini, F
Klein, M
Werner, U
Roth, W
Wilken-Schmitz, A
Tegeder, I
Rajalingam, K
Document Type
Journal Article
Date
2022-03-18
Date Accepted
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.
Citation
Science advances, 2022, 8 (11), pp. eabk1538 - ?
DOI
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Source Title
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
ISSN
eISSN
2375-2548
Collections
Research Team
Systems and Precision Cancer Medicine