Essential Role of KIBRA in Co-activator Function of Dynein Light Chain 1 in Mammalian Cells

Shaohua Peng,Amjad H. Talukder,Chunying Song,Angelika Barnekow,Petra den Hollander,Bramanandam Manavathi,Rakesh Kumar,Joachim Kremerskothen,Suresh K. Rayala

doi:10.1074/jbc.m600021200

Shaohua Peng, Amjad H. Talukder + Show 7 more

Open Access

https://doi.org/10.1074/jbc.m600021200

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Abstract

Recently dynein light chain 1 (DLC1), a cytoskeleton signaling component, has been shown to interact with and transactivate estrogen receptor-alpha (ER), leading to increased expression of ER target genes and growth stimulation of breast cancer cells. However, the molecular mechanism by which DLC1 regulates the ER pathway remains poorly understood. To gain insights into the putative mechanism, here we set out to identify novel DLC1-interacting proteins. We identified KIBRA, a WW domain- and a glutamic acid stretch-containing protein, as a DLC1-binding protein and showed that it interacts with DLC1 both in vitro and in vivo. We found that KIBRA-DLC1 complex is recruited to ER-responsive promoters. We also found that KIBRA-DLC1 interaction is mandatory for the recruitment and transactivation functions of ER or DLC1 to the target chromatin. Finally we found that KIBRA interacts with histone H3 via its glutamic acid-rich region and that such interaction might play a mechanistic role in conferring an optimal ER transactivation function as well as the proliferation of ligand-stimulated breast cancer cells. Together these findings indicate that DLC1-KIBRA interaction is essential for ER transactivation in breast cancer cells.

Highlights

With two zinc fingers, and a C-terminal ligand-binding domain with a hormone-dependent transcriptional AF2 domain [3]
Because dynein light chain 1 (DLC1) interacts with estrogen receptor-␣ (ER) and the results of our present study show that DLC1 interacts with KIBRA, we conclude that KIBRA may contribute to the functionality of the ER pathway
We found that KIBRA is recruited to estrogen response elements (EREs) sites in ER-responsive genes and potentiates ER transactivation activity upon ligand stimulation and that these responses of KIBRA depend on the presence of DLC1

Summary

Introduction

With two zinc fingers, and a C-terminal ligand-binding domain with a hormone-dependent transcriptional AF2 domain [3]. KIBRA was originally identified as a dendrin-interacting protein expressed predominantly in kidney and brain [9, 10]. It contains two N-terminal WW domains, an internal C2-like domain, and a C-terminal region rich in glutamic acids. We show that KIBRA by itself is a co-activator of ER These co-activator functions of KIBRA and DLC1 are dependent on interactions between the two proteins that involve histone H3 via the glutamic acid-rich region of KIBRA. Together our findings reveal a previously unknown connection between KIBRA, DLC1, and ER responsiveness and the existence of a regulatory pathway between histone H3-interacting KIBRA and ER via DLC1 that optimally stimulates the growth of breast cancer cells

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