Abstract
RhoGDIβ, a Rho GDP dissociation inhibitor, induced hypertrophic growth and cell migration in a cultured cardiomyoblast cell line, H9c2. We demonstrated that RhoGDIβ plays a previously undefined role in regulating Rac1 expression through transcription to induce hypertrophic growth and cell migration and that these functions are blocked by the expression of a dominant-negative form of Rac1. We also demonstrated that knockdown of RhoGDIβ expression by RNA interference blocked RhoGDIβ-induced Rac1 expression and cell migration. We demonstrated that the co-expression of ZAK and RhoGDIβ in cells resulted in an inhibition in the activity of ZAK to induce ANF expression. Knockdown of ZAK expression in ZAK-RhoGDIβ-expressing cells by ZAK-specific RNA interference restored the activities of RhoGDIβ.
Highlights
The mitogen-activated protein kinase (MAPK) signaling pathway consists of the sequentially acting upstream kinases MAPK kinase kinase (MAP3K) and MAPK kinase (MAP2K), and the downstream MAPKs, p38MAPK, extracellular signal-regulated kinase (ERK1/2), and c-jun N-terminal kinase (JNK)
Overexpression of wild-type ZAK induced apoptosis in a hepatoma cell line [3], and a recent report indicated that ZAK expression in a rat cardiac cell line, H9c2, induced hypertrophic growth and re-expression of atrial natriuretic factor (ANF) [5]
We previously demonstrated that RhoGDI is phosphorylated by ZAK in vitro
Summary
The mitogen-activated protein kinase (MAPK) signaling pathway consists of the sequentially acting upstream kinases MAPK kinase kinase (MAP3K) and MAPK kinase (MAP2K), and the downstream MAPKs, p38MAPK, extracellular signal-regulated kinase (ERK1/2), and c-jun N-terminal kinase (JNK). The mixed lineage kinases are a family of serine/threonine kinases, all of which are classified as MAP3Ks. The seven mixed lineage kinases cloned over the past several years can be classified into three subfamilies based on domain organization and sequence similarity: the MLKs (MLK1–4), the dual leucine zipperbearing kinases (DLK and LZK), and the zipper sterile- motif (SAM) kinases (ZAK and ZAK ) [1,2]. ZAK can activate the JNK pathway and the nuclear factor B (NF B) pathway [3], and it induces JNK activation through a dual phosphorylation kinase, JNKK2/MKK7 [4]. Overexpression of wild-type ZAK induced apoptosis in a hepatoma cell line [3], and a recent report indicated that ZAK expression in a rat cardiac cell line, H9c2, induced hypertrophic growth and re-expression of atrial natriuretic factor (ANF) [5].
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