Abstract
In this study we have examined the interaction between CD44 (a hyaluronan (HA) receptor) and the transforming growth factor beta (TGF-beta) receptors (a family of serine/threonine kinase membrane receptors) in human metastatic breast tumor cells (MDA-MB-231 cell line). Immunological data indicate that both CD44 and TGF-beta receptors are expressed in MDA-MB-231 cells and that CD44 is physically linked to the TGF-beta receptor I (TGF-betaRI) (and to a lesser extent to the TGF-beta receptor II (TGF-betaRII)) as a complex in vivo. Scatchard plot analyses and in vitro binding experiments show that the cytoplasmic domain of CD44 binds to TGF-betaRI at a single site with high affinity (an apparent dissociation constant (K(d)) of approximately 1.78 nm). These findings indicate that TGF-betaRI contains a CD44-binding site. Furthermore, we have found that the binding of HA to CD44 in MDA-MB-231 cells stimulates TGF-betaRI serine/threonine kinase activity which, in turn, increases Smad2/Smad3 phosphorylation and parathyroid hormone-related protein (PTH-rP) production (well known downstream effector functions of TGF-beta signaling). Most importantly, TGF-betaRI kinase activated by HA phosphorylates CD44, which enhances its binding interaction with the cytoskeletal protein, ankyrin, leading to HA-mediated breast tumor cell migration. Overexpression of TGF-betaRI by transfection of MDA-MB-231 cells with TGF-betaRIcDNA stimulates formation of the CD44.TGF-betaRI complex, the association of ankyrin with membranes, and HA-dependent/CD44-specific breast tumor migration. Taken together, these findings strongly suggest that CD44 interaction with the TGF-betaRI kinase promotes activation of multiple signaling pathways required for ankyrin-membrane interaction, tumor cell migration, and important oncogenic events (e.g. Smad2/Smad3 phosphorylation and PTH-rP production) during HA and TGF-beta-mediated metastatic breast tumor progression.
Highlights
Hyaluronan Promotes Signaling Interaction between CD44 and the Transforming Growth Factor  Receptor I in Metastatic Breast Tumor Cells*
In this study we have examined the interaction between CD44 (a hyaluronan (HA) receptor) and the transforming growth factor  (TGF-) receptors in human metastatic breast tumor cells (MDA-MB-231 cell line)
We have found that the binding of HA to CD44 in MDA-MB-231 cells stimulates TGF-RI serine/threonine kinase activity which, in turn, increases Smad2/Smad3 phosphorylation and parathyroid hormone-related protein (PTHrP) production
Summary
Hyaluronan Promotes Signaling Interaction between CD44 and the Transforming Growth Factor  Receptor I in Metastatic Breast Tumor Cells*. Overexpression of TGF-RI by transfection of MDA-MB-231 cells with TGF-RIcDNA stimulates formation of the CD441⁄7TGF-RI complex, the association of ankyrin with membranes, and HA-dependent/CD44specific breast tumor migration Taken together, these findings strongly suggest that CD44 interaction with the TGF-RI kinase promotes activation of multiple signaling pathways required for ankyrin-membrane interaction, tumor cell migration, and important oncogenic events (e.g. Smad2/Smad phosphorylation and PTH-rP production) during HA and TGF--mediated metastatic breast tumor progression. A number of studies indicate that interaction of certain extracellular matrix components (e.g. HA) with cells triggers the cytoplasmic domain of various CD44 isoforms to bind unique downstream oncogenic signaling molecules: Tiam1 [9], Vav2 [10], RhoAactivated ROK [11], c-Src kinase [12], and p185HER2 [13] and to coordinate intracellular signaling pathways (e.g. Rho/Ras signaling and receptor-linked/non-receptor-linked tyrosine kinase pathways) leading to the onset of multiple cellular functions (e.g. tumor cell growth, migration, and invasion) and breast tumor progression
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