A novel oncogene, ost, encodes a guanine nucleotide exchange factor that potentially links Rho and Rac signaling pathways.

Abstract

Transfection of NIH3T3 cells with an osteosarcoma expression cDNA library led to the appearance of foci of morphologically transformed cells which were found to harbor a novel oncogene, ost. The ost product was activated by truncation of the N‐terminal domain of the ost proto‐oncogene and was highly tumorigenic in nude mouse assays. The proto‐ost cDNA, isolated subsequently, encodes a predicted protein of 100 kDa containing DH (Db1 homology) and PH (pleckstrin homology) domains. Ost is mainly phosphorylated on serine and localized in the cytoplasm. Purified Ost protein catalyzed guanine nucleotide exchange on RhoA and Cdc42 among the Rho and Ras family members tested, indicating that Ost can activate these small GTP‐binding proteins. Ost did not detectably associate with RhoA or Cdc42, but interacted specifically with the GTP‐bound form of Rac1, suggesting that Ost can function as an effector of Rac1. These results suggest that Ost is a critical regulatory component which links pathways that signal through Rac1, RhoA and Cdc42. Of the tissues examined, expression of ost was the highest in brain and could be localized to neurons and alpha‐tanycytes, suggesting that Ost may participate in axonal transport in these specialized cells.

Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action

“…Furthermore, since Lbc is reported to be an exchange factor for RhoA (Zheng et al, 1995), Brx may be expected to function as a Rho-GEF (see below). Thus, Brx represents a novel member of the Dbl family of oncoproteins (reviewed in: Cerione and Zheng, 1996) which includes: Cdc24 and Bcr (Ron et al, 1991), Vav (Adams et al, 1992;Galland et al, 1992), Ect2 (Miki et al, 1993), Ras GRF (Shou et al, 1992), Abr (Heisterkamp et al, 1993), Tim (Chan et al, 1994), FGD1 (Pasteris et al, 1994), Lbc (Toksoz and Williams, 1994), Ost (Horii et al, 1994), Tiam-1 (Habets et al, 1994), Dbs (Whitehead et al, 1995a), Lfc (Whitehead et al, 1995b) and Lsc . The Dbl oncogene was isolated using a transfection focus assay system with DNA from a patient with di use human B cell lymphoma (Eva and Aaronson, 1985), and subsequent studies have revealed the dbl oncogene and proto-dbl oncogene (Ron et al, 1988(Ron et al, , 1991 to regulate cell growth and other diverse cellular functions (Cerione and Zheng, 1996).…”

The ras-related GTPase rac1 regulates a proliferative pathway selectively utilized by G-protein coupled receptors

“…The dbl proteins are themselves oncogenic, stimulate JNK activation and many show exchange factor activity towards the racrelated GTPases (Hart et al, 1994;Horii et al, 1994;Cerione and Zheng, 1996;Denhardt, 1996). Candidate molecules which could act upstream of these exchange factors include the src-like non-receptor tyrosine kinases, Pyk2 and the adaptor molecule shc (Dikic et al, 1996;Chen et al, 1996).…”

“…The ras proteins regulate a wide variety of cellular processes including growth and di erentiation, and constitutively activated ras is oncogenic. The rac proteins control cytoskeletal assembly (Tapon and Hall, 1997) and the exchange factors that activate rac are also oncogenic (Hart et al, 1994;Horii et al, 1994;Cerione and Zheng 1996) implying that like ras, rac also regulates mitogenic signaling pathways.…”

The RhoA‐ and CDC42‐specific exchange factor Dbs promotes expansion of immature thymocytes and deletion of double‐positive and single‐positive thymocytes

“…Dbs is an exchange factor which activates RhoA and CDC42, with weaker activation of RhoG [25][26][27]. Its rat ortholog is known as Ost [28,29]. Dbs is negatively regulated by an auto-repressive N-terminal region [25,28,29] analogous to the mode of auto-regulation of the related guanine nucleotide exchange factor (GEF), Dbl [30].…”

“…Its rat ortholog is known as Ost [28,29]. Dbs is negatively regulated by an auto-repressive N-terminal region [25,28,29] analogous to the mode of auto-regulation of the related guanine nucleotide exchange factor (GEF), Dbl [30]. The natural mechanism of activation of Dbs is unknown, but apparently involves positive regulation of the catalytic GEF domain by phosphoinositide lipids binding to the adjacent PH domain [31,32].…”