A Novel Transforming Growth Factor-β Receptor-interacting Protein That Is Also a Light Chain of the Motor Protein Dynein

Abstract

The phosphorylated, activated cytoplasmic domains of the transforming growth factor-␤ (TGF␤) receptors were used as probes to screen an expression library that was prepared from a highly TGF␤-responsive intestinal epithelial cell line. One of the TGF␤ receptor-interacting proteins isolated was identified to be the mammalian homologue of the LC7 family (mLC7) of dynein light chains (DLCs). This 11-kDa cytoplasmic protein interacts with the TGF␤ receptor complex intracellularly and is phosphorylated on serine residues after ligand-receptor engagement. Forced expression of mLC7-1 induces specific TGF␤ responses, including an activation of Jun N-terminal kinase (JNK), a phosphorylation of c-Jun, and an inhibition of cell growth. Furthermore, TGF␤ induces the recruitment of mLC7-1 to the intermediate chain of dynein. A kinase-deficient form of TGF␤ RII prevents both mLC7-1 phosphorylation and interaction with the dynein intermediate chain (DIC). This is the first demonstration of a link between cytoplasmic dynein and a natural growth inhibitory cytokine. Furthermore, our results suggest that TGF␤ pathway components may use a motor protein light chain as a receptor for the recruitment and transport of specific cargo along microtublules. INTRODUCTIONTransforming growth factor-␤ (TGF␤) is the prototype for the TGF␤ superfamily of highly conserved growth regulatory polypeptides that also includes the activins, inhibins, bone morphogenetic proteins, decapentaplegic (Dpp), nodal, Lefty, and others (Roberts, 1998;Sporn and Vilcek, 2000;Yue and Mulder, 2001). Alterations in the TGF␤ signaling components and pathways have been implicated in a vast array of human pathologies, including cancer (Massague et al., 2000;Sporn and Vilcek, 2000;Derynck et al., 2001).TGF␤ binds to two types of transmembrane serine/threonine kinase receptors (RI and RII) in a heterotetrameric complex, to activate downstream components (Roberts, 1998; Massague et al., 2000;Sporn and Vilcek, 2000;Yue and Mulder, 2001). The Smad family of signaling intermediates plays an important role in mediating TGF␤ responses (Attisano and Wrana, 2000;ten Dijke et al., 2000;Yue and Mulder, 2001). Moreover, TGF␤ has been shown to regulate Ras (Mulder and Morris, 1992;Hartsough et al., 1996;Yue et al., 1998) and several components of the mitogen-activated protein kinase (Mapk) pathways (Hartsough and Mulder, 1995;Frey and Mulder, 1997;Mulder, 2000;Sporn and Vilcek, 2000;Yue and Mulder, 2001). In addition to the Ras/Mapk and Smad pathways, several proteins have been identified based upon their interaction with the TGF␤ receptors (Yue and Mulder, 2001). Furthermore, various Smad-interacting proteins have also been identified, including SARA and Dab2, which interact with both Smads and the TGF␤ receptors (Tsukazaki et al., 1998;Hocevar et al., 2001;Yue and Mulder, 2001).Despite advances in our understanding of the mechanisms by which the Smad and Ras/Mapk cascades mediate some TGF␤ effects, these pathways seem to regulate primarily transcriptional events (Hocevar et al., 1...

The genome of the hydatid tapeworm Echinococcus granulosus

“…The E. granulosus genome had 48 DLC members (compared to 35 in Schistosoma japonicum and 29 in Schistosoma mansoni), whereas 4-7 were found in the 4 nematodes. We identified 49 cadherins in the E. granulosus genome, similar to the numbers found in schistosomes (51-65) but more than in nematodes (12)(13)(14)(15)(16)(17)(18) (Supplementary Table 22b). Cadherins belong to a class of type 1 transmembrane proteins that have important roles in cell recognition and adhesion.…”

“…npg There were more dynein light chain (DLC), dynein heavy chain (DHC) and cadherin family members in E. granulosus and schistosomes than in nematodes. Dyneins are motor proteins that act in the force-generating eukaryotic cilia and flagella and in the intracellular retrograde motility of vesicles and organelles, and DLC proteins are associated with transforming growth factor (TGF)-β signaling 15 . The E. granulosus genome had 48 DLC members (compared to 35 in Schistosoma japonicum and 29 in Schistosoma mansoni), whereas 4-7 were found in the 4 nematodes.…”

Identification of dynein light chain road block-1 as a novel interaction partner with the human reduced folate carrier

“…The dynein complex plays a role in regulating cell migration, cell division, maintenance of Golgi apparatus integrity, and transport of intracellular vesicles (22,30). DYNLRB1 has also been reported to interact with TGF-␤ membrane receptor (41) and with GTPase Rab6 (43). The existence of direct interactions between hRFC and DYNLRB1 observed in our screening was confirmed in vitro by GST-pulldown assay as well as in vivo in mammalian cells by two-hybrid Fig.…”

Signaling Receptors for TGF-β Family Members

“…This mechanism has been shown to be important during fish embryogenesis. The motor protein dynein light chain km23-1 has been shown to bind TbRII and to be phosphorylated after TGF-b stimulation (Tang et al 2002). km23-1 promotes both Smad-dependent (Jin et al 2007a) and Smad-independent signaling.…”