Identification of a truncated {beta}1-chimaerin variant that inactivates nuclear Rac1 [Signal Transduction]: β1-chimaerin belongs to the chimaerin family of GTPase-activating proteins (GAPs) and is encoded by the CHN2 gene that also encodes the β2- and β3-chimaerin isoforms. All chimaerin isoforms have a C1 domain that binds diacylglycerol (DAG), as well as the tumor-promoting phorbol esters, and a catalytic GAP domain that inactivates the small GTPase Rac. Nuclear Rac has emerged as a key regulator of various cell functions including cell division, and has a pathological role by promoting tumorigenesis and metastasis. However, how nuclear Rac is regulated has not been fully addressed. Here, using several approaches, including siRNA-mediated gene silencing, confocal microscopy, and subcellular fractionation we identified a nuclear variant of β1-chimaerin, β1-Δ7p-chimaerin, that participates in the regulation of nuclear Rac1. We show that β1-Δ7p-chimaerin is a truncated variant generated by alternative splicing at a cryptic splice site in exon 7. We found that, unlike other chimaerin isoforms, β1-Δ7p-chimaerin lacks a functional C1 domain and is not regulated by DAG. We found that β1-Δ7p-chimaerin localizes to the nucleus via a nuclear localization signal (NLS) in its N-terminus. We also identified a key nuclear export signal (NES) in β1-chimaerin that is absent in β1-Δ7p-chimaerin, causing the nuclear retention of this truncated variant. Functionally analyses revealed that β1-Δ7p-chimaerin inactivates nuclear Rac and negatively regulates the cell cycle. Our results provide important insights into the diversity of chimaerin Rac-GAP regulation and function, and highlight a potential mechanism of nuclear Rac inactivation that may play significant roles in pathologies such as cancer.
Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,
Ετικέτες
Κυριακή 22 Δεκεμβρίου 2019
Identification of a truncated {beta}1-chimaerin variant that inactivates nuclear Rac1 [Signal Transduction]
Αναρτήθηκε από
Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,
στις
10:50 μ.μ.
Ετικέτες
00302841026182,
00306932607174,
alsfakia@gmail.com,
Anapafseos 5 Agios Nikolaos 72100 Crete Greece,
Medicine by Alexandros G. Sfakianakis,
Telephone consultation 11855 int 1193
Εγγραφή σε:
Σχόλια ανάρτησης (Atom)
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου