RAP1GDS1 (RAP1, GTP-GDP dissociation stimulator 1)

4q23

RAP1, GTP-GDP dissociation stimulator 1 (RAP1GDS1) is a gene that encodes a protein that functions as a stimulatory GDP/GTP exchange protein with GTPase activity. Fusions, missense mutations, nonsense mutations, silent mutations, frameshift deletions, and in-frame deletions are observed in cancers such as endometrial cancer , intestinal cancer, and skin cancer .

RAP1GDS1 encodes a 558-amino acid protein with a molecular mass of 61.1 kD. The product of the RAP1GDS1 gene, usually referred to as smgGDS, has guanine nucleotide exchange factor activity. It stimulates the conversion of inactive GDP-bound from small GTPases to the active GTP-bound form. It has been speculated that smgGDS might also play a role in nucleocytoplasmic transport, as smgGDS is composed of multiple armadillo repeats that are thought to mediate protein-protein interactions.
SmgGDS has been described as a "master regulator" of small GTPases, such as RHOA , RAC1 , RAP1A , RAP1B , and KRAS . SmgGDS controls the activities of these GTPases through several mechanisms, most notably by controlling their prenylation and trafficking to cell membranes. The ability of smgGDS to regulate the cell cycle in multiple cancer cell lines with different mutational profiles indicates the importance of this protein as a key regulator of malignancy. SmgGDS is overexpressed in multiple types of cancer, including non-small cell lung carcinoma , prostate cancer , pancreatic cancer and breast cancer , making SmgGDS is an attractive target for cancer therapeutics.

NUP98 (nucleoporin 98 kDa)

11p15.4

NUP98 is one of several genes located in the imprinted gene domain of chromosome 11p15. Combined haploinsufficiency of NUP98 and RAE1 has been shown to result in premature separation of sister chromatids, leading to severe aneuploidy. NUP98 plays roles in gene expression, mitotic spindle formation, and cell cycle progression.

NUP98 gene is fused to a large number of "partner genes" caused primarily by balanced translocations and inversions which are associated with a wide variety of hematological malignancies including AML and MDS (de novo and therapy related), CML-blast crisis, and pre T- ALL. To date, no NUP98 fusion gene has been described in B-cell malignancies. At least 30 different partner genes are reported to fuse with NUP98; 50% of which are homeobox genes. Approximately 10% of patients with NUP98 fusions have T-ALL; most commonly, these malignancies are associated with NUP98-RAP1GDS1 gene fusions. This suggests that different partner genes are associated with different leukemia, although such associations are rarely exclusive. Although NUP98 breakpoints in these translocations are variable located between introns 9 to 14, a chimeric transcript consisting of the 5 portion of NUP98 fused in-frame to the 3 portion of the partner genes is generated in all.

NUP98 gene encodes two alternatively spliced mRNA variants: NUP98 and NUP98-NUP96 that are cleaved to produce two distinct nucleoporins, NUP98 and NUP96. The NUP98 is a 98 kDa protein component of the nuclear pore complex (NPC) family which is involved in the trafficking of RNA and protein between the nucleus and cytoplasm. The NUP98 protein contains two partially characterized functional domains: a GLFG repeat region, which serves as a nuclear transport receptor docking surface, and a GLEBS domain, which mediates the interaction with the RAE1 mRNA nuclear export factor. Both domains are located within the N-terminal portion of NUP98. The chimeric NUP98 protein that results from translocations always retains the intact N-terminal GLFG repeats of NUP98 and the C-terminal domain of the partner protein. NUP96 is a scaffold component of the NPC.