Extracellular PKCδ signals to epidermal growth factor receptor for tumor proliferation in liver cancer cells

Abstract

Protein kinase C delta (PKCδ) is a multifunctional PKC family member and has been implicated in many types of cancers, including liver cancer. Recently, we have reported that PKCδ is secreted from liver cancer cells, and involved in cell proliferation and tumor growth. However, it remains unclear whether the extracellular PKCδ directly regulates cell surface growth factor receptors. Here, we identify epidermal growth factor receptor (EGFR) as a novel interacting protein of the cell surface PKCδ in liver cancer cells. Imaging studies showed that secreted PKCδ interacted with EGFR‐expressing cells in both autocrine and paracrine manners. Biochemical analysis revealed that PKCδ bound to the extracellular domain of EGFR. We further found that a part of the amino acid sequence on the C‐terminal region of PKCδ was similar to the putative EGFR binding site of EGF. In this regard, the point mutant of PKCδ in the binding site lacked the ability to bind to the extracellular domain of EGFR. Upon an extracellular PKCδ‐EGFR association, ERK1/2 activation, downstream of EGFR signaling, was apparently induced in liver cancer cells. This study indicates that extracellular PKCδ behaves as a growth factor and provides a molecular basis for extracellular PKCδ‐targeting therapy for liver cancer.

Extended-synaptotagmin 1 engages in unconventional protein secretion mediated via SEC22B+vesicle pathway in liver cancer

“…Previous reports have reported the involvement of extracellularly secreted cytosolic proteins, including PKCδ, in tumorigenesis ( 18 , 19 , 28 ). To confirm the relationship between PKCδ binding to E-Syt1 and tumorigenesis, PKCδ KO cells were reintroduced with the WT or the Δ601–676 mutant of PKCδ.…”

“…Previous studies have reported several cytosolic proteins that are actively secreted from cancer cell lines, such as protein kinase Cδ (PKCδ), importin α1, nucleolin (NCL), and HSP90, and their involvement in tumor growth ( 18 – 22 ). In particular, extracellular PKCδ binds to cell surface glypican-3 and EGF receptors in liver cancer cells and activates growth signals, such as ERK1/2 ( 18 , 19 ).…”

“…Previous studies have reported several cytosolic proteins that are actively secreted from cancer cell lines, such as protein kinase Cδ (PKCδ), importin α1, nucleolin (NCL), and HSP90, and their involvement in tumor growth ( 18 – 22 ). In particular, extracellular PKCδ binds to cell surface glypican-3 and EGF receptors in liver cancer cells and activates growth signals, such as ERK1/2 ( 18 , 19 ). The secretory events of some cytosolic proteins, such as PKCδ and HSP90, have been suggested to initiate from the cytosol; however, it is unclear as to which intracellular membranes are involved in cytosolic protein secretion.…”

Transcriptional Response to Standard AML Drugs Identifies Synergistic Combinations

“…It is also involved in the DNA damage tolerance pathway by rescuing DNA damage-stalled replication fork [ 43 ]. Protein kinase C delta (PRKCD) is a serine/threonine-protein kinase involved in several processes, including DNA damage response and apoptosis, and is also associated with EGFR signaling [ 44 , 45 ]. The enhanced synergy of cancer cells harboring PRKDC mutation to the daunorubicin-EGFR inhibitor combination could result from inhibiting nonhomologous end joining-mediated DNA double-strand breaks repair [ 44 ].…”

Extended-Synaptotagmin 1 Enhances Liver Cancer Progression Mediated by the Unconventional Secretion of Cytosolic Proteins

“…Recently, the extracellular secretion of intracellular proteins without signal peptides, that is, leaderless proteins, termed unconventional secretion, has been reported in inflammation, neurodegenerative diseases, and cancer [ 2 , 3 ]. Many studies have identified several leaderless cytoplasmic proteins in the culture media of cancer cells, including protein kinase C delta (PKCδ), importin α1, and HSP90 [ 4 , 5 , 6 , 7 ]. Clinical studies have shown that serum PKCδ levels are significantly higher in patients with hepatocellular carcinoma (HCC) than in normal individuals or those with chronic liver disease (chronic hepatitis and cirrhosis) [ 8 ].…”