RIP1, a kinase on the crossroads of a cell's decision to live or die

Abstract

Binding of inflammatory cytokines to their receptors, stimulation of pathogen recognition receptors by pathogen-associated molecular patterns, and DNA damage induce specific signalling events. A cell that is exposed to these signals can respond by activation of NF-jB, mitogen-activated protein kinases and interferon regulatory factors, resulting in the upregulation of antiapoptotic proteins and of several cytokines. The consequent survival may or may not be accompanied by an inflammatory response. Alternatively, a cell can also activate death-signalling pathways, resulting in apoptosis or alternative cell death such as necrosis or autophagic cell death. Interplay between survival and death-promoting complexes continues as they compete with each other until one eventually dominates and determines the cell's fate. RIP1 is a crucial adaptor kinase on the crossroad of these stress-induced signalling pathways and a cell's decision to live or die. Following different upstream signals, particular RIP1-containing complexes are formed; these initiate only a limited number of cellular responses. In this review, we describe how RIP1 acts as a key integrator of signalling pathways initiated by stimulation of death receptors, bacterial or viral infection, genotoxic stress and T-cell homeostasis. Cell Death and Differentiation (2007) 14, 400-410. doi:10.1038/sj.cdd.4402085Receptor interacting protein (RIP) kinases constitute a family of seven members, all of which contain a kinase domain (KD) (Figure 1a). They are crucial regulators of cell survival and death 1 (Figure 2). Based on sequence similarities, mode of regulation and substrate specificities of their catalytic domain, RIP kinases are classified as serine/threonine kinases and are closely related to members of the interleukin-1-receptorassociated kinase (IRAK) family. RIP1 and RIP2 (CARDIAK/ RICK) also bear a C-terminal domain belonging to the death domain (DD) superfamily, namely, a DD and a caspase recruitment domain (CARD), respectively, allowing recruitment to large protein complexes initiating different signalling pathways. The unique C-terminus of RIP3 bears a RIP homotypic interaction motif (RHIM), which is also present in the intermediate domain (ID) of RIP1. This RHIM domain is sufficient for interaction of RIP1 with RIP3. 1 RIP4 (DIK/PKK) and RIP5 (SgK288) are characterized by the presence of ankyrin repeats in their C-terminal domains. 1 RIP6 (LRRK1) and RIP7 (LRRK2) are RIP members containing a leucine-rich repeat (LRR) motif 1 that may be involved in recognition of pathogen-, damage-or stress-associated molecular patterns (PAMP, DAMP, SAMP). In addition, they harbor Roc/COR domains (Ras of complex proteins/C-terminal of Roc). Binding of GTP to the GTPase-like Roc domain leads to the stimulation of LRRK1 kinase activity. 2 Mutation analysis indicated that the COR domain might be important for transmitting the stimulating signal to the KD. 2 The function of RIP6 and RIP7 is yet unknown; however, mutations in the human LRRK2 gene are associated with both fam...

TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme

“…IRAK-1 and IRAK-4 mediate TLR/IL-1R signaling, and their counterparts in TNF-R signaling are RIP1 and most likely RIP4 [105]. However, RIP1 seems to be a more universal player, which can also take part in TLR signaling and many other receptor specific signaling pathways to NF-kB [106]. TLR/IL-1R as well as TNF-R signaling does not depend on the catalytic activity of the above-mentioned kinases, although they are functionally active.…”

Multiple death pathways in TNF-treated fibroblasts: RIP3- and RIP1-dependent and independent routes

“…While receptorinteracting protein 1 (RIP1) can participate in signaling for both apoptosis and necrosis [3,4], recent studies by us and by others have shown that RIP3 is essential for TNF-induced necroptosis [5][6][7] and has no role in TNFinduced apoptosis [6,7]. Classification of TNF-induced cell death in a number of cell lines, such as L929 and murine embryonic fibroblasts (MEFs), has been made based on morphological and/or biochemical parameters [2,[7][8][9][10].…”

cIAP1 and TAK1 protect cells from TNF-induced necrosis by preventing RIP1/RIP3-dependent reactive oxygen species production

“…[7][8][9][10] Interestingly, RIP1 has also been implicated in the apoptotic process triggered by several death receptors. 11 This suggests that apoptosis and necrosis, initially defined as mutually exclusive cell death processes, might paradoxically share several regulatory components.…”