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Review
. 2020 Jan 23:7:371.
doi: 10.3389/fcell.2019.00371. eCollection 2019.

Lipid Transfer Proteins and Membrane Contact Sites in Human Cancer

Diego Peretti  1 , SoHui Kim  2 , Roberta Tufi  3 , Sima Lev  4
Affiliations
Review

Lipid Transfer Proteins and Membrane Contact Sites in Human Cancer

Diego Peretti et al. Front Cell Dev Biol. .

Abstract

Lipid-transfer proteins (LTPs) were initially discovered as cytosolic factors that facilitate lipid transport between membrane bilayers in vitro. Since then, many LTPs have been isolated from bacteria, plants, yeast, and mammals, and extensively studied in cell-free systems and intact cells. A major advance in the LTP field was associated with the discovery of intracellular membrane contact sites (MCSs), small cytosolic gaps between the endoplasmic reticulum (ER) and other cellular membranes, which accelerate lipid transfer by LTPs. As LTPs modulate the distribution of lipids within cellular membranes, and many lipid species function as second messengers in key signaling pathways that control cell survival, proliferation, and migration, LTPs have been implicated in cancer-associated signal transduction cascades. Increasing evidence suggests that LTPs play an important role in cancer progression and metastasis. This review describes how different LTPs as well as MCSs can contribute to cell transformation and malignant phenotype, and discusses how "aberrant" MCSs are associated with tumorigenesis in human.

Keywords: LTPs; MCSs; calcium; cancer; lipids.

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Figures

FIGURE 1
FIGURE 1
Phosphatidylinositols transfer proteins. (A) PI-transfer proteins. The five human PI-transfer proteins can be divided into small proteins consisting of a single PI-transfer domain (PITD) including PITPα/β and PITPNC1, and the multi-domains containing proteins Nir2 and Nir3. Shown are the PITD, the FFAT motif, DDHD, and the C-terminal LNS2 (Lipin/Nde1/Smp2) domain. Glycine rich region is found only in Nir3 (Lev, 2004). PITPNC1 phosphorylation sites (S274 and S299), which bind 14-3-3, are represented as red dots on PITPNC1 protein (Halberg et al., 2016). (B) TIPE3, a PIP2, and PIP3 transfer protein. TIPE is the only protein that is known to transfer phosphoinositides. It preferentially binds PIP2 and PIP3, and contributes to increase their levels at the PM by mediating efficient supply of PIP2 and presenting it to PI3K to produce PIP3 (Fayngerts et al., 2014). The numbers at the right side of each protein indicate the length of each protein in amino acids.
FIGURE 2
FIGURE 2
The START proteins. Fifteen START proteins in human are grouped into six subfamilies. Three groups share the indicated lipid binding/transfer specificity of START domain, while the other three groups share the indicated functional domains. All members have their START domain at the C-terminal region. Among 15 START proteins, two of them, STARD3 and CERT, contain FFAT motif. STARD3, STARD10, STARD7, and STARD5 are found to be highly expressed and connected to poor prognosis in various cancers including breast cancer, gestational trophoblastic tumor (Clark, 2012). On the other hand, the expression of all members of Rho-GTPase subgroup, STARD8/12/13, STARD9, and STARD15 are reported to be decreased in cancer (Clark, 2012). The number at the right side of each C-terminal represents the length of each protein in amino acids.
FIGURE 3
FIGURE 3
Endoplasmic reticulum-endosome MCSs in normal and cancer cells overexpressing STARD3. The sterol-transfer protein STARD3 promotes the formation of MCSs between late endosomes (LE) and the endoplasmic reticulum (ER), where it mediates cholesterol transport. Tethering of ER and LE occurs through the interaction of the LE-membrane anchored STARD3 (via its FFAT-like motif) with the integral ER proteins VAPs. In cancer cells, overexpression of STARD3 possibly induces the formation of aberrant LE-ER MCSs thereby inhibiting further endosomal maturation. Endosomal maturation is commonly associated with Rab5 to Rab7 switch and with PI3P to PI(3,5)P2. MSP, major sperm protein domain.
FIGURE 4
FIGURE 4
Phosphoinositides, sphingolipids, and cholesterol regulate cell growth, motility, and invasion. The depicted cellular pathways are regulated by phosphoinositeds (PIns), sphingolipids, and cholesterol and can influence cell growth, motility, invasion, or apoptotic cell death. LTPs are labeled in blue and include PIns-transfer proteins, ceramide transfer protein (CERT), and various cholesterol transfer proteins of the START and OSBP/ORP family. PLC, phospholipase C; PKC, protein kinase C; DAG, diacylglycerol; S6K, S6 kinase; SM, sphingomyelin; SMS, SM synthase; S1P, sphingosine 1-phosphate; C1P, ceramide 1-phosphate; LPP, lipid phosphate phosphatase; SPP-1, S1P phosphatase-1; CERK, ceramide kinase; SphK, sphingosine kinase.
FIGURE 5
FIGURE 5
Mitochondria-associated ER membranes in normal versus cancer cells. Schematic cartoon illustrating ER-mitochondria (MAMs) tethering proteins. MAMs regulate lipid transfer and play an important role in Ca2+ homeostasis by orchestrating Ca2+ shuttling from ER to mitochondria. Normal cells rely on oxidative phosphorylation for energy production, and possess normal MAM configuration, which promotes apoptotic cell death in response to calcium overloading. Conversely in cancer cells, which use the glycolytic pathway to produce ATP, expression level of tethering proteins is altered and “aberrant” MAMs are formed. In most cases, the ER-mitochondria contact is reduced and, hence, also the mitochondrial calcium uptake, favoring cell survival and resistance to chemotherapeutic drugs. Multiple proteins are involved in ER-mitochondria tethering (Sassano et al., 2017), those that are described in the text and the figures are: TMX1, thioredoxin related transmembrane protein 1; PTPIP51, protein tyrosine phosphatase-interacting protein 51; VAPB, VAMP-associated protein B; Mfn1/2, Mitofusin 1/2; PERK, protein kinase RNA-like ER kinase; GRP75, glucose-regulated protein 75; IP3R, IP3 (inositol 1,4,5-trisphosphate) receptor; VDAC, voltage-dependent anion channel; PACS2, phosphofurin acidic cluster sorting protein 2.
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