CD98: Key Functions in Amino Acid Transport and Immune Regulation

CD98 is a multifunctional protein involved in amino acid transport and immune regulation. It plays a crucial role in cellular metabolism, adhesion, and signaling, making it essential for various physiological processes. Its influence extends to immunity, cancer, and metabolic disorders, making it a key focus of scientific research.

Understanding CD98’s functions provides insight into cellular communication and adaptation. Researchers continue to explore its therapeutic potential, particularly in immune-related diseases and tumors.

Molecular Structure And Localization

CD98, also known as SLC3A2 or 4F2hc, is a type II transmembrane glycoprotein composed of a heavy chain (CD98hc) and a light chain (CD98lc). The heavy chain is a single-pass transmembrane protein with a large extracellular domain that facilitates protein interactions, while the light chain, part of the solute carrier (SLC) family, is responsible for amino acid transport. These subunits form a heterodimeric complex through a disulfide bond, enabling CD98 to function in both transport and signaling. Glycosylation of CD98hc is crucial for its stability and localization within the plasma membrane.

CD98 is highly expressed in proliferative cells, including epithelial tissues, activated lymphocytes, and certain stem cell populations. It is particularly abundant in metabolically active organs such as the intestine, kidney, and placenta, where it supports amino acid uptake. Endothelial cells also express CD98, contributing to adhesion and nutrient exchange. Its upregulation in rapidly dividing cells has been observed in various pathological conditions.

At the subcellular level, CD98 is primarily localized to the plasma membrane, where it associates with lipid rafts—membrane microdomains involved in signal transduction. This positioning enables CD98 to participate in cellular communication and metabolism. It is also found in the endoplasmic reticulum and Golgi apparatus, where it undergoes post-translational modifications necessary for functional maturation.

Role In Amino Acid Transport

CD98 facilitates amino acid transport by acting as a chaperone for solute carrier (SLC) transporters, particularly those in the SLC7 family. These transporters, also known as light chains, mediate the translocation of neutral and cationic amino acids across the plasma membrane. The heavy chain stabilizes these transporters and enhances their surface expression, ensuring efficient uptake of amino acids essential for metabolism and growth. This role is well-characterized in system L transporters, such as LAT1 (SLC7A5) and LAT2 (SLC7A8), which exchange large neutral amino acids like leucine, phenylalanine, and tryptophan.

CD98-associated transport is especially vital in tissues with high metabolic demands. In the intestine, it aids dietary amino acid absorption, while in the kidneys, it supports reabsorption to prevent nutrient loss. In rapidly proliferating cells, including tumors, CD98-mediated transport fuels biosynthetic pathways. Leucine uptake, in particular, regulates the mechanistic target of rapamycin (mTOR) pathway, which governs cell growth and protein synthesis.

Beyond transport, CD98 is involved in amino acid sensing, modulating intracellular concentrations to regulate pathways such as the general control nonderepressible 2 (GCN2) and amino acid response (AAR) pathways. These mechanisms help cells adapt to nutrient availability, ensuring metabolic flexibility under varying conditions.

Interaction With Integrins

CD98 modulates integrin function, influencing cell adhesion, migration, and survival. Integrins mediate interactions between cells and the extracellular matrix (ECM), transmitting signals that regulate cellular behavior. CD98 enhances integrin clustering and activation, strengthening adhesion, which is essential in tissues experiencing mechanical stress, such as the vascular endothelium and epithelial layers.

Beyond adhesion, CD98 facilitates integrin-dependent signaling pathways that regulate proliferation and survival. Its interaction with integrins recruits intracellular signaling proteins like focal adhesion kinase (FAK) and Src family kinases, initiating cascades such as the phosphoinositide 3-kinase (PI3K)/Akt pathway, which promotes cell survival. This role is particularly relevant in wound healing and tissue remodeling, where efficient cell migration and proliferation are required.

CD98 also influences mechanotransduction by stabilizing integrin-actin linkages, reinforcing the cytoskeletal network and enabling cells to respond to mechanical cues. In endothelial cells, this regulation affects vascular homeostasis by adjusting responses to blood flow and shear stress. Experimental models have shown that loss of CD98 function reduces integrin signaling, impairing actin organization and cellular adaptation to mechanical stimuli.

Functions In Immune Regulation

CD98 is critical for immune cell activation, proliferation, and signaling. Its expression is elevated in activated lymphocytes, where it supports metabolic reprogramming necessary for rapid expansion and effector function. In T cells, CD98 enhances amino acid transport and integrin-mediated adhesion, facilitating the transition from a resting to an active state for effective immune responses.

It also plays a role in immune cell adhesion and migration, strengthening leukocyte-endothelial interactions and aiding immune cell infiltration into inflamed tissues. In macrophages and dendritic cells, CD98 influences antigen presentation by optimizing cellular interactions with other immune components. This function is particularly relevant in chronic inflammatory conditions, where CD98 expression affects immune activity. Experimental models indicate that disrupting CD98 impairs immune cell trafficking and alters inflammatory responses.

Dysregulation In Some Conditions

CD98 is frequently dysregulated in pathological conditions, including cancer, metabolic disorders, and inflammatory diseases. Understanding these disruptions provides insight into its role in disease progression and its potential as a therapeutic target.

In oncology, CD98 overexpression is a hallmark of aggressive tumors, including colorectal, breast, and glioblastoma. Its role in amino acid uptake and integrin-mediated adhesion supports tumor growth and metastasis. Elevated CD98 levels are associated with increased mTOR activation, driving cancer cell proliferation and survival. Additionally, its role in integrin signaling promotes epithelial-mesenchymal transition (EMT), enabling cancer cells to invade surrounding tissues. Studies show that blocking CD98 function reduces tumor growth and metastatic potential, making it a promising target for cancer therapy. Experimental treatments aim to inhibit CD98-mediated amino acid transport to starve tumor cells or disrupt its integrin interactions to limit invasiveness.

CD98 dysfunction is also linked to metabolic disorders, particularly those involving amino acid imbalances. Given its role in leucine transport, disruptions in CD98 activity can affect mTOR signaling, leading to metabolic irregularities. In obesity and type 2 diabetes, altered CD98 expression has been associated with insulin resistance, likely due to its impact on nutrient sensing pathways. Research suggests that modifying CD98 activity could help restore metabolic balance by improving amino acid transport and reducing inflammation associated with metabolic syndrome.