Role of Receptor Interacting Protein (RIP) kinases in cancer - PubMed (original) (raw)

Review

Role of Receptor Interacting Protein (RIP) kinases in cancer

Kaylee Ermine et al. Genes Dis. 2021.

Abstract

The Receptor Interacting Protein (RIP) kinase family consists of seven Serine/Threonine kinases, which plays a key signaling role in cell survival and cell death. Each RIP family member contains a conserved kinase domain and other domains that determine the specific kinase function through protein-protein interactions. RIP1 and RIP3 are best known for their critical roles in necroptosis, programmed necrosis and a non-apoptotic inflammatory cell death process. Dysregulation of RIP kinases contributes to a variety of pathogenic conditions such as inflammatory diseases, neurological diseases, and cancer. In cancer cells, alterations of RIP kinases at genetic, epigenetic and expression levels are frequently found, and suggested to promote tumor progression and metastasis, escape of antitumor immune response, and therapeutic resistance. However, RIP kinases can be either pro-tumor or anti-tumor depending on specific tumor types and cellular contexts. Therapeutic agents for targeting RIP kinases have been tested in clinical trials mainly for inflammatory diseases. Deregulated expression of these kinases in different types of cancer suggests that they represent attractive therapeutic targets. The focus of this review is to outline the role of RIP kinases in cancer, highlighting potential opportunities to manipulate these proteins in cancer treatment.

Keywords: Cancer; Cell death; Immune response; Necroptosis; RIP kinases.

© 2021 Chongqing Medical University. Production and hosting by Elsevier B.V.

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Figures

Fig. 1

Figure 1

Sequence homology of the kinase domains of RIP family members. (A) Sequence alignment of RIP kinase domains generated through UniProtKB. Dark grey (∗) indicates fully conserved residues, medium grey (:) indicates conserved residues with strong similarity, and light grey (.) indicates conserved residues with weak similarity. Two different RIP5s have been described, including Dusty Protein Kinase (Dusty) and Sugen kinase 288 (SgK288). (B) Percent similarity relative to RIP1 calculated through UniProtKB. Each kinase domain has approximately 20–30% similarity to RIP1. (C) Phylogenetic tree of RIP kinases generated through UniProtKB.

Fig. 2

Figure 2

Structure of RIP Kinases. RIP1-RIP5 (SgK288) contain N-terminal kinase domains. RIP1 contains a C-terminal death domain, while RIP2 contains a C-terminal caspase-recruiting domain (CARD). Both RIP1 and RIP3 are RHIM-containing proteins, which is located within the intermediate domain. RIP4, RIP5 (SgK288), and RIP6 contain ankyrin repeats. RIP6 and RIP7 both contain leucine-rich repeats (LRRs) and a Ros of complex proteins (Roc)/C-terminus of Roc (COR) domain. RIP7 also contains WD40 repeats. The number of amino acids (AAs) in each protein is indicated on the right.

Fig. 3

Figure 3

RIP1 and RIP3 are critical mediators of necroptosis. TNF-α binds to the TNFR, promoting formation of Complex I, consisting of TRADD, TRAF2, cIAP1/2, and RIP1. cIAP1/2 ubiquitinates (Ub) RIP1, which can promote cell survival through the NF-κB and MAPK pathways. Upon de-ubiquitination by CYLD, RIP1 can interact with caspase-8 and FADD, promoting apoptosis. When caspase is inhibited, RIP1 can promote necroptosis by interacting with RIP3, leading to its autophosphorylation. Phosphorylated RIP3 recruits and phosphorylates MLKL, which translocates and oligomerizes at the plasma membrane, inducing rupture.

References

    1. Stanger B.Z., Leder P., Lee T.H., Kim E., Seed B. RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death. Cell. 1995;81(4):513–523. -PubMed
    1. Holler N., Zaru R., Micheau O., et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol. 2000;1(6):489–495. -PubMed
    1. Cho Y.S., Challa S., Moquin D., et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009;137(6):1112–1123. -PMC -PubMed
    1. He S., Wang L., Miao L., et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009;137(6):1100–1111. -PubMed
    1. Zhang D.W., Shao J., Lin J., et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science. 2009;325(5938):332–336. -PubMed

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