Etk, a Btk family tyrosine kinase, mediates cellular transformation by linking Src to STAT3 activation.

Etk (also called Bmx) is a member of the Btk tyrosine kinase family and is expressed in a variety of hematopoietic, epithelial, and endothelial cells. We have explored biological functions, regulators, and effectors of Etk. Coexpression of v-Src and Etk led to a transphosphorylation on tyrosine 566 of Etk and subsequent autophosphorylation. These events correlated with a substantial increase in the kinase activity of Etk. STAT3, which was previously shown to be activated by Etk, associated with Etk in vivo. To investigate whether Etk could mediate v-Src-induced activation of STAT3 and cell transformation, we overexpressed a dominant-negative mutant of Etk in an immortalized, untransformed rat liver epithelial cell line, WB, which contains endogenous Etk. Dominant-negative inactivation of Etk not only blocked v-Src-induced tyrosine phosphorylation and activation of STAT3 but also caused a great reduction in the transforming activity of v-Src. In NIH3T3 cells, although Etk did not itself induce transformation, it effectively enhanced the transforming ability of a partially active c-Src mutant (c-Src378G). Furthermore, Etk activated STAT3-mediated gene expression in synergy with this Src mutant. Our findings thus indicate that Etk is a critical mediator of Src-induced cell transformation and STAT3 activation. The role of STAT3 in Etk-mediated transformation was also examined. Expression of Etk in a human hepatoma cell line Hep3B resulted in a significant increase in its transforming ability, and this effect was abrogated by dominant-negative inhibition of STAT3. These data strongly suggest that Etk links Src to STAT3 activation. Furthermore, Src-Etk-STAT3 is an important pathway in cellular transformation.

[Experimental research on inhibitory effect of alcohol extracts from Loranthus yadoriki Sieb. on coxsackie B3 virus].

OBJECTIVE: To investigate the antiviral effect of two components (B and C) in the alcohol extracts from Loranthus yadoriki Sieb for development of new antiviral drugs for coxsackie B3 virus(CVB3). METHOD: Using ribavirin as positive control, the plaque reduction assay was adopted for pharmadynamic detection. RESULTS: In the HEp-2 cell system, with respect to direct virucidal activity and the inhibition on CVB3 infection and multiplication, ED50s of component B were 2.32 micrograms.ml-1, 0.24 microgram.ml-1 and 1.91 micrograms.ml-1, respectively and those of component C, 1.44 micrograms.ml-1, 2.06 micrograms.ml-1 and 3.70 micrograms.ml-1 respectively. For the inhibition on multiplication of CVB3, ED50 of ribavirin was 7.55 micrograms.ml-1. CONCLUSION: Treatment indexes (TI) of the direct virucidal activity and inhibitory effects of component B on CVB3 infection and multiplication 22.6, 219 and 27.5 respectively; component C, 115, 165 and 21.6; inhibition of ribavirin on CVB3 is 38, which is comparable to those of components B and C. It is thus suggested that the anti-CVB3 action of components B and C in the alcohol extracts from Loranthus yadoriki Sieb deserves to be exploited.

N-acyl phenylalanine analogues as potent small molecule VLA-4 antagonists.

We have identified a series of low molecular weight (Mr < 500) N-acylphenylalanines that are effective inhibitors of the VCAM-VLA-4 interaction. Investigation of the SAR of the N-acyl moiety led to the identification of N-benzylpyroglutamyl derivatives as being particularly potent.

N-benzylpyroglutamyl-L-phenylalanine derivatives as VCAM/VLA-4 antagonists.

A series of N-(N-benzylpyroglutamyl)-4-substituted-L-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. Analogues substituted by electron deficient benzoylamino groups bearing bulky ortho substituents had low-nM potency in an ELISA assay and low-microM activity in a cell based assay.