Matricellular Proteins: A Sticky Affair with Cancers
Figure 1
Summarized the signaling mechanisms of various matricellular proteins contributing to cancer progression. ANGPTL4 binds to both integrins and ECM to promote tumor survival, tumor invasion and modulate the availability of ECM. (a) ANGPTL4 interacting with integrin activates Rac1 and NADPH oxidase, which generate high level of . This will further activating the Src machinery and stimulates its downstream PI3K/PKB mediated survival pathway. (b) ANGPTL4 interacting with integrin also activates FAK-src-PAK1 signaling and PKC/14-3-3 mediated pathway which modulate cell migration via integrin internalization. (c) ANGPTL4 binds specific matrix proteins and delays their degradation by proteases. However, this association does not interfere with integrin-matrix protein recognition unlike TNC. (d) TNC can compete with fibronectin to bind integrin α5β1 coreceptor, syndecan-4, which blocks the activation of promigratory FAK/RhoA/ROCK signaling pathway. (e) TNC can activate Wnt signaling by downregulating the soluble inhibitor DKK-1, thus resulted in nuclear localization of β-catenin. Nuclear β-catenin interacts with TCF/LEF to promote the expression of genes contributing to tumor formation, survival, and metastasis. OPN can interact with several (f) integrins and also (g) CD44 family of receptors. These complexes are able to mediate tumor cell survival through PI3k/PKB pathway activation and motility for detachment or invasion of tumor cell through the activation of AP-1-dependent gene expression via the MEK/Erk pathway. (h) Certain domains of TSP1 (such as NoC1) can bind directly to integrins to activate signaling proteins such as Erk1/2 and paxillin which modulates tumor formation. (i) TSP1 binding to CD36 activates Fyn and p38 MAPK pathway which is essential for the suppression of tumor growth. (j) TSP1 can also bind CD47, to modulate sGC and cGMP-dependent protein kinase, thus inhibiting the NO signaling necessary for angiogenesis. (k) TSP-1 association with CD47 or direct competitive binding of TSP1 to VEGF can inhibit VEGFR2 signaling. VEGFR2 activates the PI3K/PKB pathway which leads to activation of eNOS/NO signaling. Simultaneously, VEGFR2 can also signal through PLCγ, which further increases AMPK-mediated eNOS phosphorylation and NO production. eNOS/NO signaling regulate downstream targets that increase endothelial cell proliferation, migration, survival, and permeability. (l) TSP1 can activate TGFβ/smad pathway to inhibit tumor cell proliferation and induce apoptosis. (m) SPARC binds integrin, inducing ILK/FAK/PKB activation to increase cell migration. (n) Cyr61 can promote tumor cell proliferation and survival through the activation of integrin mediated signaling pathway either by direct binding with integrin or integrin-syndecan4. The downstream intracellular events may be mediated through the FAK/PI3K/PKB signaling pathway, resulting in either activation of the NF-κB survival pathway or phosphorylation of GSK3β and nuclear translocation of β-catenin for cell proliferation. (o) Cyr61 allows protein degradation of E-cadherin leading to β-catenin translocation.
