Mammary-derived growth inhibitor (MDGI) interacts with integrin α-subunits and suppresses integrin activity and invasion

Abstract

The majority of mortality associated with cancer is due to formation of metastases from the primary tumor. Adhesion mediated by different integrin heterodimers has an important role during cell migration and invasion. Protein interactions with the b1-integrin cytoplasmic tail are known to influence integrin affinity for extracellular ligands, but regulating binding partners for the a-subunit cytoplasmic tails have remained elusive. In this study, we show that mammary-derived growth inhibitor (MDGI) (also known as FABP-3 or H-FABP) binds directly to the cytoplasmic tail of integrin a-subunits and its expression inhibits integrin activity. In breast cancer cell lines, MDGI expression correlates with suppression of the active conformation of integrins. This results in reduced integrin adhesion to type I collagen and fibronectin and inhibition of cell migration and invasion. In tissue microarray of 1331 breast cancer patients, patients with MDGI-positive tumors had more favorable 10-year distant disease-free survival compared with patients with MDGI-negative tumors. Our data indicate that MDGI is a novel interacting partner for integrin a-subunits, and its expression modulates integrin activity and suppresses cell invasion in breast cancer patients. Retained MDGI expression is associated with favorable prognosis.

Negative regulators of integrin activity

“…MDGI overexpression reduces adhesion of cells to type I collagen and fibronectin and impairs both migration and invasion specifically in human breast cancer cell lines but not in other cell types (Nevo et al, 2010). These effects are due to an MDGI-induced significant reduction in the active b1integrin conformation on the cell surface as determined with conformationsensitive antibodies against b1 integrin (Nevo et al, 2010). The exact molecular details of the function of MDGI as a negative regulator of integrin activity remain unsolved, but MDGI overexpression in MDA-MB-231 breast cancer cells reduces the association of kindlin with active b1 integrin, suggesting that MDGI binding to cytoplasmic integrin-a tails could indirectly hamper the binding of integrin agonists to integrin-b tails (Nevo et al, 2010).…”

“…The aintegrins that the respective integrin activator or inactivator has been shown to bind is given in parentheses. The a-integrin-interacting proteins are SHARPIN (Rantala et al, 2011), Rab21 and p120RasGAP (also known as RAS p21 protein activator, RASA1) (Mai et al, 2011;, GIPC1 (Valdembri et al, 2009), MDGI (Nevo et al, 2010), (Barry et al, 2002) and nischarin (Alahari and Nasrallah, 2004). …”

“…MDGI is almost ubiquitously expressed, and is particularly abundant in muscle and mammary gland (Haunerland and Spener, 2004). Recently, MDGI has been shown to interact with several different integrin a-subunits (a1, a2, a5, a6, a10 and a11), probably through the highly conserved WKxGFFKR sequence that is present in most, if not all, a-subunits (Nevo et al, 2010). MDGI overexpression reduces adhesion of cells to type I collagen and fibronectin and impairs both migration and invasion specifically in human breast cancer cell lines but not in other cell types (Nevo et al, 2010).…”

“…Recently, MDGI has been shown to interact with several different integrin a-subunits (a1, a2, a5, a6, a10 and a11), probably through the highly conserved WKxGFFKR sequence that is present in most, if not all, a-subunits (Nevo et al, 2010). MDGI overexpression reduces adhesion of cells to type I collagen and fibronectin and impairs both migration and invasion specifically in human breast cancer cell lines but not in other cell types (Nevo et al, 2010). These effects are due to an MDGI-induced significant reduction in the active b1integrin conformation on the cell surface as determined with conformationsensitive antibodies against b1 integrin (Nevo et al, 2010).…”

“…These effects are due to an MDGI-induced significant reduction in the active b1integrin conformation on the cell surface as determined with conformationsensitive antibodies against b1 integrin (Nevo et al, 2010). The exact molecular details of the function of MDGI as a negative regulator of integrin activity remain unsolved, but MDGI overexpression in MDA-MB-231 breast cancer cells reduces the association of kindlin with active b1 integrin, suggesting that MDGI binding to cytoplasmic integrin-a tails could indirectly hamper the binding of integrin agonists to integrin-b tails (Nevo et al, 2010). It remains unclear why these effects of MDGI on integrin activity are specific to breast cancer cells.…”