Neuropilin as new co-receptor of leptin – NRPLEP

Neuropilin-1 (NRP1) is a pleiotropic membrane receptor involved in axon guidance in the central nervous system and in angiogenesis by interacting with specific co-receptors such as plexins or VEGF receptors. NRP1 has also been reported to be involved in the regulation of hematopoiesis and in cancer progression.

During our investigation of the role of bone marrow adipocytes on hematopoiesis, we have shown that adipocytes through the production of leptin inhibit the production of factors stimulating granulopoiesis including G-CSF. In addition, we have shown that NRP1 is involved in this process but not the well-known NRP1 ligands (VEGF and semaphorin). Interestingly by studying the expression of NRP1 in hematopoietic cells we found a new isoform of NRP1 deleted of 7 amino-acids (delta7). These findings led us to raise the hypothesis that NRP1 and/or its isoform delta7 could be a co-receptor of OBR the cognate receptor of leptin, and are the basis of the present project.

Leptin and OBR have been initially associated with the regulation of food intake, and subsequently with hematopoiesis and angiogenesis during cancer progression. In contrast to OBR, NRP1 is unable to promote cellular signaling events on its own but functions rather as a co-receptor of signaling competent receptors such as plexins or VEGF receptors. We have currently cumulated clear evidence for the existence of OBR/NRP1/leptin complex.

The aims of the present project are

a) to provide a detailed biochemical characterization of this newly discovered molecular complex NRP1/OBR/leptin (interacting properties, signal transduction, trafficking)

b) to investigate the role of this complex in the regulation of granulopoiesis and in cancer progression by using a model of breast cancer in which leptin and NRP1 have been previously shown to play a role in tumor progression and drug resistance.
Depending on the obtained results, the OBR/NP1 (WT and/or delta7) complex may become a new therapeutic target in pathological conditions including, congenital as well as acquired neutropenia, and in breast cancer progression as well as other tumors.