CD33 reponses are blocked by SOCS3 through accelerated proteasomal-mediated turnover

CD33 is a member of the sialic acid–binding immunoglobulin-like lectin (Siglec) family of inhibitory receptors and a therapeutic target for acute myeloid leukemia (AML). CD33 contains a cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM), which can recruit SHP-1 and SHP-2. How CD33 expression is regulated is unclear. Suppressor of cytokine signaling 3 (SOCS3) is expressed in response to cytokines, LPS, and other PAMPs, and competes with SHP-1/2 binding to ITIMs of cytokine receptors, thereby inhibiting signaling. In this study, using peptide pull-down experiments, we found that SOCS3 can specifically bind to the phosphorylated ITIM of CD33. Additionally, following cross-linking SOCS3 can recruit the ECS E3 ligase resulting in accelerated proteasomal degradation of both CD33 and SOCS3. Our data suggest that the tyrosine motifs in CD33 are not important for internalization, while they are required for degradation. Moreover, SOCS3 inhibited the CD33-induced block on cytokine-induced proliferation. This is the first receptor shown to be degraded by SOCS3 and where SOCS3 and its target protein are degraded concomitantly. Our findings clearly suggest that during an inflammatory response, the inhibitory receptor CD33 is lost by this mechanism. Moreover, this has important clinical implications as tumors expressing SOCS3 may be refractory to -CD33 therapy.

Dynamic Knowledge Creation Through Value Management Teams

With the intention of introducing unique and value-added products to the market, organizations have become more conscious of how to best create knowledge as reported by Ganesh Bhatt in 2000 in 'Information dynamics, learning and knowledge creation in organizations'. Knowledge creation is recognized as having an important role in generating and sustaining a competitive advantage as well as in meeting organizational goals, as reported by Aleda Roth and her colleagues in 1994 in 'The knowledge factory for accelerated learning practices.' One of the successful ingredients of value management (VM) is its utilization of diverse knowledge resources, drawing upon different organizational functions, professional disciplines, and stakeholders, in a facilitated team process. Multidisciplinary VM study teams are viewed as having high potential to innovate due to their heterogeneous nature. This paper looks at one of the VM workshop's major benefits, namely, knowledge creation. A case study approach was used to explore the nature, processes, and issues associated with fostering a dynamic knowledge creation capability within VM teams. The results indicate that the dynamic knowledge creating process is embedded in and influenced by managing team constellation, creating shared awareness, developing shared understanding, and producing aligned action. The catalysts that can speed up the processes are open dialogue and discussion among participants. This process is enhanced by the use of facilitators, skilled at extracting knowledge.