10.3389/fphys.2019.00388.s002
Ivan K. Popov
Ivan K.
Popov
Susan M. Hiatt
Susan M.
Hiatt
Sandra Whalen
Sandra
Whalen
Boris Keren
Boris
Keren
Claudia Ruivenkamp
Claudia
Ruivenkamp
Arie van Haeringen
Arie
van Haeringen
Mei-Jan Chen
Mei-Jan
Chen
Gregory M. Cooper
Gregory
M. Cooper
Bruce R. Korf
Bruce R.
Korf
Chenbei Chang
Chenbei
Chang
Image_1_A YWHAZ Variant Associated With Cardiofaciocutaneous Syndrome Activates the RAF-ERK Pathway.JPEG
Frontiers
2019
YWHAZ
CFC
RASopathy
Raf
Erk activation
Xenopus
2019-04-09 04:22:17
Figure
https://frontiersin.figshare.com/articles/figure/Image_1_A_YWHAZ_Variant_Associated_With_Cardiofaciocutaneous_Syndrome_Activates_the_RAF-ERK_Pathway_JPEG/7968302
<p>Cardiofaciocutaneous (CFC) syndrome is a genetic disorder characterized by distinctive facial features, congenital heart defects, and skin abnormalities. Several germline gain-of-function mutations in the RAS/RAF/MEK/ERK pathway are associated with the disease, including KRAS, BRAF, MEK1, and MEK2. CFC syndrome thus belongs to a group of disorders known as RASopathies, which are all caused by pathogenic mutations in various genes encoding components of the RAS pathway. We recently identified novel variants in YWHAZ, a 14-3-3 family member, in individuals with a phenotype consistent with CFC that may potentially be deleterious and disease-causing. In the current study, we take advantage of the vertebrate model Xenopus laevis to analyze the functional consequence of a particular YWHAZ variant, S230W, and investigate the molecular mechanisms underlying its activity. We show that compared with wild type YWHAZ, the S230W variant induces severe embryonic defects when ectopically expressed in early Xenopus embryos. The S230W variant also rescues the defects induced by a dominant negative FGF receptor more efficiently and enhances Raf-stimulated Erk phosphorylation to a higher level than wild type YWHAZ. Although neither YWHAZ nor the variant promotes membrane recruitment of Raf proteins, the variant binds to more Raf and escapes phosphorylation by casein kinase 1a. Our data provide strong support to the hypothesis that the S230W variant of YWHAZ is a gain-of-function mutation in the RAS-ERK pathway and may underlie a CFC phenotype.</p>