The multifunctional
cell-surface protein dipeptidyl peptidase IV (DPPIV/CD26) is aberrantly expressed in many
cancers and plays a key role in
tumorigenesis and
metastasis. Its diverse cellular roles include modulation of
chemokine activity by cleaving
dipeptides from the
chemokine NH(2)-terminus, perturbation of extracellular
nucleoside metabolism by binding the ecto-
enzyme adenosine deaminase, and interaction with the extracellular matrix by
binding proteins such as
collagen and
fibronectin. We have recently shown that DPPIV can be downregulated from the cell surface of HT-29
colorectal carcinoma cells by
adenosine, which is a metabolite that becomes concentrated in the extracellular fluid of hypoxic solid
tumors. Most of the known responses to
adenosine are mediated through four different subtypes of
G protein-coupled
adenosine receptors: A(1), A(2A), A(2B), and A(3). We report here that
adenosine downregulation of DPPIV from the surface of HT-29 cells occurs independently of these classic receptor subtypes, and is mediated by a novel cell-surface mechanism that induces an increase in
protein tyrosine phosphatase activity. The increase in
protein tyrosine phosphatase activity leads to a decrease in the
tyrosine phosphorylation of ERK1/2 MAP
kinase that in turn links to the decline in DPPIV
mRNA and
protein. The downregulation of DPPIV occurs independently of changes in the activities of
protein kinases A or C,
phosphatidylinositol 3-kinase, other
serine/
threonine phosphatases, or the p38 or JNK MAP
kinases. This novel action of
adenosine has implications for our ability to manipulate
adenosine-dependent events within the solid tumor microenvironment.