Progranulin Oncogenic Network in Solid Tumors

Abstract

Progranulin is a pleiotropic growth factor with important physiological roles in embryogenesis and maintenance of adult tissue homeostasis. While-progranulin deficiency is associated with a broad range of pathological conditions affecting the brain, such as frontotemporal dementia and neuronal ceroid lipofuscinosis, progranulin upregulation characterizes many tumors, including brain tumors, multiple myeloma, leiomyosarcoma, mesothelioma and epithelial cancers such as ovarian, liver, breast, bladder, adrenal, prostate and kidney carcinomas. The increase of progranulin levels in tumors might have diagnostic and prognostic significance. In cancer, progranulin has a pro-tumorigenic role by promoting cancer cell proliferation, migration, invasiveness, anchorage-independent growth and resistance to chemotherapy. In addition, progranulin regulates the tumor microenvironment, affects the function of cancer-associated fibroblasts, and modulates tumor immune surveillance. However, the molecular mechanisms of progranulin oncogenic function are not fully elucidated. In bladder cancer, progranulin action relies on the activation of its functional signaling receptor EphA2. Notably, more recent data suggest that progranulin can also modulate a functional crosstalk between multiple receptor-tyrosine kinases, demonstrating a more complex and context-dependent role of progranulin in cancer. Here, we will review what is currently known about the function of progranulin in tumors, with a focus on its molecular mechanisms of action and regulation.

Keywords: RTKs; progranulin; solid tumors.

Figure 1

Progranulin structure, processing and trafficking. The growth factor progranulin is a modular protein containing seven and half non-identical, cysteine-rich tandem repeats, known as granulin domains. Progranulin can be processed by several proteases into single granulin modules. Progranulin is released into the extracellular environment by regulated exocytosis. Extracellular progranulin can be internalized in a sortilin- or prosaposin-dependent manner and sorted into lysosomes but can also reach the lysosomes diverting from the secretory pathway. In lysosomes, progranulin is processed by cathepsin L into granulins. Whether progranulin might be endocytosed in a sortilin- and prosaposin-independent manner through the binding to other receptors is still not fully defined. ER: endoplasmic reticulum. TGN: trans-Golgi network.

Figure 2

Progranulin signaling in cancer. Progranulin oncogenic signaling is highly dependent on progranulin-dependent activation of AKT and/or MAPK signaling pathways. In colorectal cancer, progranulin promotes AKT activation in a TNFR2-dependent manner. In prostate cancer, sortilin acts as a negative regulator of progranulin by promoting progranulin internalization and degradation, leading to the inhibition of the AKT pathway. In turn, progranulin mediates sortilin ubiquitination and degradation to sustain its pro-oncogenic activity. In bladder cancer, progranulin binds to and activates EphA2, leading to AKT and MAPK activation. In turn, AKT and MAPK sustain EphA2 phosphorylation at Ser897. In mesothelioma, progranulin-dependent activation of the AKT and MAPK signaling pathways relies on EGFR and RYK. Progranulin directly interacts with TNFRs, sortilin and EphA2. Whether progranulin promotes EGFR and RYK phosphorylation and activation directly by physically interacting with the receptors, or in an indirect manner, or whether progranulin promotes the formation of a complex including EGFR, RYK and EphA2 requires further investigation.

Figure 3

Progranulin modulates FAK activity. In bladder cancer, progranulin-dependent activation of ERK1/2 promotes the formation of a complex containing FAK, paxillin and ERK1/2, thereby promoting cell motility. In addition, in bladder cancer, progranulin interacts with the F-actin-binding protein drebrin, promoting F-actin remodeling. However, the mechanism by which progranulin interacts with drebrin is still unknown and could be dependent on receptor-mediated progranulin internalization. In mesothelioma cells, progranulin modulates the phosphorylation of FAK, affecting the dynamics of focal adhesion assembly/disassembly and F-actin remodeling. RYK action in progranulin-dependent modulation of FAK in mesothelioma is still not well defined.