Discoidin domain receptor tyrosine kinases: new players in cancer progression

Abstract

Almost all human cancers display dysregulated expression and/or function of one or more receptor tyrosine kinases (RTKs). The strong causative association between altered RTK function and cancer progression has been translated into novel therapeutic strategies that target these cell surface receptors in cancer. Yet, the full spectrum of RTKs that may alter the oncogenic process is not completely understood. Accumulating evidence suggests that a unique set of RTKs known as the discoidin domain receptors (DDRs) play a key role in cancer progression by regulating the interactions of tumor cells with their surrounding collagen matrix. The DDRs are the only RTKs that specifically bind to and are activated by collagen. DDRs control cell and tissue homeostasis by acting as collagen sensors, transducing signals that regulate cell polarity, tissue morphogenesis, and cell differentiation. In cancer, DDRs are hijacked by tumor cells to disrupt normal cell-matrix communication and initiate pro-migratory and pro-invasive programs. Importantly, several cancer types exhibit DDR mutations, which are thought to alter receptor function and contribute to cancer progression. Other evidence suggests that the actions of DDRs in cancer are complex, either promoting or suppressing tumor cell behavior in a DDR type/isoform specific- and context-dependent manner. Thus, there is still a considerable gap in our knowledge of DDR actions in cancer tissues. This review summarizes and discusses the current knowledge on DDR expression and function in cancer. It is hoped that this effort will encourage more research into these poorly understood but unique RTKs, which have the potential of becoming novel therapeutic targets in cancer.

Fig. 1

Domain structure of DDRs. Residues that are added as a result of alternative splicing are indicated by dark green boxes within the corresponding domain. Red and blue circles indicate putative N-glycosylation and O-glycosylation sites, respectively. Mutated DDR residues, which were identified in samples of Non-Small Cell Lung Carcinomas (black) and Acute Myeloid Leukemia (red), are indicated. aa, amino acids; JM, juxtamembrane region, and TM, transmembrane region.

Fig. 2

Identified phospho-DDR1 interactions. The PTB domain in ShcA and the SH2 domain in Csk and Nck2 directly interact with phospho-DDR1. In the case of PLC-γ, Vav1/2, SFKs, and PI3K, which contain both SH2 and SH3 domains, the interacting domain(s) is unknown. TM, transmembrane domain; SH2, Src homology 2 domain; SH3, Src homology 3 domain; PTB, phospho-tyrosine binding domain; PLCγ, phospholipase C γ; ShcA, SH2 containing transforming protein A; Csk, C-terminal Src kinase; SFKs, Src family tyrosine kinases; PI3K, phosphoinositide 3 kinase; SHP-2, SH2 containing protein tyrosine phosphatase 2; SHIP-1/2, SH2-containing inositol polyphosphate 5-phosphatase 1/2, and STATs, Signal transducer and activator of transcription. The indicated amino acid annotations refer to the DDR1b isoform.

Fig. 3

Reported DDR-initiated signaling pathways in cancer cells. Solid lines indicate direct interactions or effects. Dashed lines represent indirect interactions or effects that are mediated through one or more intermediate steps. Unknown interactions (direct or indirect) are indicated with a question mark. Arrows pointing to DDRs indicate pathways involved in DDR activation and arrows pointing away from DDRs indicate pathways triggered by activated DDRs. Activated DDRs are indicated with a yellow star. The red box depicts processes that are suppressed by DDR signaling. The green box depicts processes that are promoted by DDRs. The orange box depicts processes that are either suppressed or promoted by DDR signaling under different contexts. The grey box depicts processes that are associated with DDR expression/function but the signaling pathways or mechanisms activated by DDRs in these processes have not been worked out yet. Some DDR1 interactions, e.g. with Nck1/2, SHP-2 and Csk, are not shown since downstream signaling pathways triggered by these interactions are unknown in the context of cancer.