In the last decades increasing importance has been attributed to the
Insulin/
Insulin-like Growth Factor signaling (IIGFs) in
cancer development, progression and resistance to
therapy. In fact, IIGFs is often deregulated in
cancer. In particular, the mitogenic
insulin receptor isoform A (IR-A) and the
insulin-like growth factor receptor (IGF-1R) are frequently overexpressed in
cancer together with their cognate
ligands IGF-1 and
IGF-2. Recently, we identified
discoidin domain receptor 1 (DDR1) as a new IR-A interacting
protein. DDR1, a non-
integrin collagen tyrosine kinase receptor, is overexpressed in several
malignancies and plays a role in
cancer progression and
metastasis. Herein, we review recent findings indicating that DDR1 is as a novel modulator of IR and IGF-1R expression and function. DDR1 functionally interacts with IR and IGF-1R and enhances the biological actions of
insulin,
IGF-1 and
IGF-2. Conversely, DDR1 is upregulated by
IGF-1,
IGF-2 and
insulin through the PI3K/AKT/miR-199a-5p circuit. Furthermore, we discuss the role of the non-canonical
estrogen receptor GPER1 in the DDR1-IIGFs crosstalk. These data suggest a wider role of DDR1 as a regulator of cell response to
hormones,
growth factors, and signals coming from the extracellular matrix.