Chromosomal amplification of leucine-rich repeat kinase-2 (LRRK2) is required for oncogenic MET signaling in papillary renal and thyroid carcinomas

Abstract

The receptor tyrosine kinase MET is frequently amplified in human tumors, resulting in high cell surface densities and constitutive activation even in the absence of growth factor stimulation by its endogenous ligand, hepatocyte growth factor (HGF). We sought to identify mechanisms of signaling crosstalk that promote MET activation by searching for kinases that are coordinately dysregulated with wild-type MET in human tumors. Our bioinformatic analysis identified leucine-rich repeat kinase-2 (LRRK2), which is amplified and overexpressed in papillary renal and thyroid carcinomas. Downregulation of LRRK2 in cultured tumor cells compromises MET activation and selectively reduces downstream MET signaling to mTOR and STAT3. Loss of these critical mitogenic pathways induces cell cycle arrest and cell death due to loss of ATP production, indicating that MET and LRRK2 cooperate to promote efficient tumor cell growth and survival in these cancers.kidney cancer | kinase bioinformatics | thyroid cancer C onstitutive and unregulated activation of receptor tyrosine kinases (RTKs) is a common oncogenic mechanism in human cancers (1). Oncogenic activation of RTKs can be achieved by several different mechanisms that include somatic mutation, genetic amplification, autocrine growth factor stimulation, dysregulation of receptor trafficking pathways, or crosstalk with other kinase signaling cascades (2, 3). In many cases these separate mechanisms work in tandem to promote increased oncogenic signaling by an RTK. Prominent examples of these combinatorial mechanisms include coordinate amplification and somatic mutation of EGF receptor (EGFR) in lung cancer and coordinate overexpression of several different growth factor receptors and their cognate ligands in melanoma (4, 5).The receptor tyrosine kinase MET, located at 7q31, is frequently amplified and highly activated in human tumors (6, 7). Although activating mutations to MET have been discovered, they are found in relatively few human tumor types (8-10). Tumors that contain genomic amplification of MET may also overexpress its ligand, hepatocyte growth factor (HGF), thereby establishing an autocrine signaling loop to achieve constitutive MET activation (11-13). However, a number of tumor types demonstrate genomic amplification of MET without somatic mutation or coordinate overexpression of HGF, suggesting the existence of alternative mechanisms that activate MET in the absence of activating mutations or abundant ligand (6).In this study we sought to identify oncogenic mechanisms that promote ligand-independent MET activation by searching for kinases that are coordinately dysregulated with MET in sporadic type 1 papillary renal cell carcinoma (RCC), which is a prototypical tumor type driven by amplification and overexpression of MET (14,15). Unlike hereditary cases of papillary RCC in which MET activation is driven by specific point mutations, sporadic type 1 papillary tumors rarely demonstrate MET mutations (16, 17). Because HGF is also not significantly expressed in these tumors...

Measuring intratumor heterogeneity by network entropy using RNA-seq data

“…Recent cohort study revealed the relationship between parkinson’s disease and cancer72. Also in molecular-level studies, the PARK2 and LRRK2 genes well known in parkinson’s disease were revealed that those genes were related with cell cycle pathways7374.…”

MET Is a Potential Target across All Papillary Renal Cell Carcinomas: Result from a Large Molecular Study of pRCC with CGH Array and Matching Gene Expression Array

“…Looyenga and colleagues (20) identified LRRK2 as a mechanism of signaling cross-talk that promotes MET activation, tumor cell growth, and survival in papillary renal and thyroid carcinomas. We confirmed that LRRK2 is amplified and upregulated across pRCC and highly correlates with MET expression.…”

“…In addition, it has been previously demonstrated that MET-triggered pathway implicates several upstream regulators and coreceptors that are physically associated with MET either at the cell surface or intracytoplasmic domain that might consequently induce MET transactivation (15). For instance, leucine-rich repeat kinase 2 (LRRK2) has recently been reported as a required kinase for MET oncogenic signaling in pRCC (20). We therefore investigated the potential impact of both ligand and coactivators required for MET activation in pRCC.…”

LRRK2 and autophagy: a common pathway for disease

“…Many functional roles for LRRK2 have been suggested, including vesicular trafficking and endocytosis [11,12], protein synthesis [13], immune response regulation [14], inflammation [15] and cytoskeleton homoeostasis [16]. Finally, LRRK2 has been associated with TNFα (tumour necrosis factor α) [17], Met [18], interferon γ [19] and MAPK (mitogen-activated protein kinase) [20] signalling pathways. However, there is still no consensus on LRRK2 function, and its physiological role(s) remain to be elucidated.…”