APRO4 negatively regulates Src tyrosine kinase activity in PC12 cells

Abstract

The Src nonreceptor tyrosine kinase plays an important role in multiple signalling pathways that regulate several cellular functions including proliferation, differentiation and transformation. The activity of Src is tightly regulated in vivo and can be modulated by interactions of its SH2 and SH3 domains with high-affinity ligands. APRO4 (anti-proliferative 4) belongs to a new antiproliferative gene family involved in the negative control of the cell cycle. This report shows that APRO4 associates with Src via its C-terminal proline-rich domain, and downregulates Src kinase activity. Moreover, overexpression of APRO4 leads to inhibition of neurite outgrowth and Ras/MAP kinase signalling in PC12 cells. Furthermore, the kinetics of endogenous Src inactivation correlates with an increase in endogenous APRO4 co-immunoprecipitation in FGF-stimulated PC12 cells. Finally, downregulation of endogenous APRO4 by expression of antisense RNA induces the activation of Src and spontaneous formation of neurites in PC12 cells. Therefore, by controlling the basal threshold of Src activity, APRO4 constitutes an important negative regulatory mechanism for Src-mediated signalling.

Molecular genetic analysis of Down syndrome

“…This gene is located in the gene poor region of HSA21 and has been shown to undergo loss of heterozygosity in some breast cancers (Ohgaki et al 2001). BTG3 has been reported to down-regulate the activity of src tyrosine kinase (Rahmani 2006). BTG3 is also a target of p53 and inhibits the activity of the E2F1 transcription factor (Ou et al 2007), both properties consistent with BTG3 having tumor suppressor activity.…”

“…One deletion spans a region from DNA marker RH46998 on the centromeric side to D21S11 (inclusive) on the telomeric side. Of some interest, one gene that is deleted is the BTG3 gene, a suspected tumor suppressor gene hypothesized to play a role in the decreased risk of solid tumors seen in individuals with DS (Yu et al 2008;Majid et al 2009;Rahmani 2006;Ou et al 2007) (discussed below). Moreover, the BTG3 gene is very tightly regulated in DS cells (Prandini et al 2007).…”

Genistein reverses hypermethylation and induces active histone modifications in tumor suppressor gene B‐Cell translocation gene 3 in prostate cancer

“…The protein also seemed to be antiproliferative, as its introduction into NIH3T3 cells reduced BrdU incorporation 5 . More recently, BTG3 was found to associate with and inhibit Src tyrosine kinase in PC12 cells 6 and a direct transcriptional target of p53 7 .…”

The suppressing effects of BTG3 expression on aggressive behaviors and phenotypes of colorectal cancer: Anin vitroandvivostudy

“…BTG3 can interact with E2F1 to suppress the binding of the E2F1-DP1 complex to DNA duplex, resulting in cellular S-phase arrest [5]. BTG3 also interacts with Smad8 receptor- regulated Smad transcription factor [6], and with src to suppress Ras/MAP kinase signaling [7]. BTG3 can be phosphorylated and activated via the interaction with checkpoint kinase 1 (CHK1).…”