Review
Introduction
RAGE and Soluble RAGE
RAGE Signaling Perpetuates the Immune and Inflammatory Response
RAGE Ligands
Overview of HMGB1 and the HMG Protein Family
Name (alt. name) | Chromosome | Post-translational modifications | Sub-cellular localization | Normal tissue expression | Expression in cancer |
---|---|---|---|---|---|
HMGA1a (HMG-I, HMG-I/Y), HMGA1b (HMG-Y), HMGA1c (HMG-I/R) | 6p21 | Highly modified with numerous sites of phosphorylation, acetylation and/or methylation. Possibly SUMOylated and ADP-ribosylated. | Nucleus but has role in shuttling HIPK2 (homeodomain-interacting protein kinase 2) to the cytosol | Abundantly expressed in undifferentiated and proliferating embryonic cells but usually undetectable in adult tissue | Overexpressed in malignant epithelial tumors and leukemia |
HMGA2 (HMGI-C, HMGIC) | 12q14-15 | Phosphorylated | Nucleus – the second AT-hook is necessary and sufficient for nuclear localization | See HMGA1's | Invasive front of carcinomas. A splice variant without the acidic tail is found in some benign tumors. |
HMGB1 (HMG1, Amphoterin) | 13q12 | Acetylated, methylated, phosphorylated, and/or ADP-ribosylated when actively secreted. An acidic tail-deleted isoform has been purified from calf thymus | Often nuclear but translocates to the cytosol and is actively secreted and passively released | Abundantly expressed in all tissues except neurons. Highest levels in thymus, liver and pancreas. | See Table 2 |
HMGB2 (HMG2) | 4q31 | Phosphorylated on up to three residues | see HMGB1 | Thymus and testes | Squamous cell carcinoma of the skin, ovarian cancer |
HMGB3 (HMG-4, HMG-2a) | Xq28 | Lymphoid organs. mRNA detected in embryos and mouse bone marrow | mRNA detected in small cell and non-small cell lung carcinomas (SCLC, NSCLC) | ||
HMGN1 (HMG14) | 21q22.3 | Acetylated, highly phosphorylated, | nucleus | Weakly expressed in most tissues | |
HMGN2 (HMG17) | 1p36.1-1p35 | Acetylated | nucleus | Weakly expressed in most tissues, but strong in thymus, bone marrow, thyroid and pituitary gland | |
HMGN3 (TRIP-7) | 6q14.1 | nucleus | Abundantly expressed in kidney, skeletal muscle and heart. Low levels found in lung, liver and pancreas | ||
HMGN4 (HMG17, L3 NHC) | 6p21.3 | Highly phosphorylated | nucleus | Weakly expressed in all tissues |
Biochemistry of HMGB1
Evolution of HMGB1
Normal/healthy levels of HMGB1
HMGB1 and RAGE in cancer and inflammation
Inflammatory state, disease or cancer | Effect of RAGE/HMGB1 |
---|---|
Colon cancer | Co-expression of RAGE and HMGB1 leads to enhanced migration and invasion by colon cancer cell lines. Increased RAGE expression in colon cancer has been associated with atypia, adenoma size, and metastasis to other organs. Stage I tumors have relatively low % of tumors expressing, Stage IV virtually universal expression |
Prostate cancer | Co-expression of RAGE and HMGB1 has been found in a majority of metastatic cases, in tumor cells and associated stromal cells. |
Pancreatic cancer | Enhanced expression of RAGE and HMGB1 in the setting of metastases. |
Lung and esophageal cancers | Higher tumor stage is characterized by downregulation of RAGE. |
Inflammatory Arthritis | HMGB1 is overexpressed. RAGE binding, as other receptors, results in: macrophage stimulation, induction of TNFα and IL-6, maturation of DCs, Th1 cell responses, stimulation of CD4+ and CD8+ cells, and amplification of response to local cytokines. |
Sepsis | HMGB1 propagates inflammatory responses and is a significant RAGE ligand in the setting of sepsis and acute inflammation. HMGB1 is an apparent autocrine/paracrine regulator of monocyte invasion, involving RAGE mediated transmigration through the endothelium. |
Is HMGB1 the lone RAGE activator of the HMG family?
S100 Proteins as RAGE ligands and their role in Inflammation
Name | Chrom. | RAGE binding | p53 binding | Normal tissue expression | Expression in cancer | Cancer notes |
---|---|---|---|---|---|---|
S100A1
| 1q21 |
Possibly, (antagonizes S100A4-RAGE interactions)
| Yes – TET and NRD | Highest in heart, also expressed in kidney, liver, skin, brain, lung, stomach, testis, muscle, small intestine, thymus and spleen | Renal carcinoma | |
S100A2
| 1q21 |
Not observed
| Yes – TET and NRD | Kerotinocytes, breast epithelial tissue, smooth muscle cells and liver | Thyroid, prostate, lung, oral, and breast carcinomas; melanoma | Mostly down-regulated but upregulated in some cancer types |
S100A3
| 1q21 |
Not observed
| Differentiating cuticular cells in the hair follicile | |||
S100A4
| 1q21 |
Yes, coexpressed with RAGE in lung and breast cancer
| Chondrocytes, astrocytes, Schwann cells, and other neuronal cells | Thyroid, breast and colorectal carcinomas; melanoma; bladder and lung cancers | Overexpression is associated with metastases and poor prognosis | |
S100A5
| 1q21 |
Not observed
| Limited areas of the brain | Astrocytic tumors | Overexpressed | |
S100A6
| 1q21 |
Yes, coexpressed with RAGE in lung and breast cancer
| Yes – TET | Neurons of restricted regions of the brain | Breast cancer, colorectal carcinoma | Not found in healthy breast or colorectal |
S100A7/A7A
| 1q21 |
Yes, Zinc dependant activation
| Kerotinocytes, dermal smooth muscle cells | Breast carcinoma, bladder and skin cancers | Not expressed in non-cancer tissues except for skin | |
S100A8/A9
| 1q21 |
Possibly (activates NF-kB in endothelial cells)
| Expressed and secreted by neutrophils | Breast and colorectal carcinomas, gastric cancer | Upregulated in premetastatic stage, then downregulated | |
S100A9
| 1q21 |
See S100A8
| See S100A8 | See S100A8 | ||
S100A10
| 1q21 |
Not observed
| Several tissues, highest in lung, kidney, and intestine | |||
S100A11
| 1q21 |
Yes – inflammation induced chondrcyte hypertrophy
| Yes – TET | Keratinocytes | Colorectal, breast, and renal carcinomas; bladder, prostate, and gastric cancers | Decreased expression is an early event in bladder carcinoma, high expression is associated with better prognosis in bladder and renal cancer patients but worse prognosis in prostate and breast |
S100A12
| 1q21 |
Yes – Inflammatory processes (activates endothelial cells and leukocytes)
| Granulocytes, keratinocytes | Expressed in acute, chronic, and allergic inflammation | ||
S100A13
| 1q21 |
Yes – stimulates its own uptake by cells
| Broadly expressed in endothelial cells, but not vascular smooth muscle cells | Upregulated in endometrial lesions | ||
S100A14
| 1q21 |
Not observed
| Broadly expressed in many tissues, but not detected in brain, skeletal muscle, spleen, peripheral blood leukocytes | Overexpressed in ovary, breast and uterus tumors, Down-regulated in kidney, rectum and colon tumors | ||
S100A15
(name withdrawn, see S100A7)
| ||||||
S100A16
| 1q21 |
Not observed
| Broadly expressed with highest levels esophagus, lowest in lung, brain, pancreas and skeletal muscle | Upregulated in lung, pancreas, bladder, thyroid and ovarian tumors | ||
S100B
| 21q22 |
Yes – RAGE -dependant, cytochrome C mediated activation of caspase-3
| Yes – TET and NRG | Astrocytes | Melanoma | Overexpressed in melanoma |
S100G
| Xp22 |
Not observed
| Pancreas, intestine, mineralized tissues | Pancreatic cancer | Overexpressed >100-fold | |
S100P
| 4p16 |
Yes – stimulates cell proliferation and survival
| Placenta | Prostate and gastric cancers | Overexpressed | |
S100Z
| 5q14 |
Not observed
| Pancreas, lung, placenta, and spleen | Decreased expression in cancer |
S100 Proteins are not universal RAGE ligands
Non-ligands of RAGE: S100A2, A3, A5, A10, A14, A16, G, Z
Possible ligands of RAGE: S100A1, S100A8/9
Ligands of RAGE: S100A4, A6, A7/A7A/A15, A11, A12, A13, B, P
S100A4
S100A6
S100A7/S100A7A/S100A15
S100A11
S100A12/EN-RAGE
S100A13
S100B
S100P
S100 Proteins – subtle differences translate to large changes in RAGE binding
RAGE and Abeta
RAGE and Collagen
AGEs
RAGE and AGEs in the Redox Environment
RAGE Ligands in Neurobiology
RAGE in Epithelial Malignancies
RAGE and Immune Cells
Immune cell | Associated RAGE ligand | Effects on immune cells | Associated diseases |
---|---|---|---|
Neutrophils | AGE, Mac-1 | Neutrophils adhere to RAGE-transfected cells but free AGE reduces this adherence and the ability of neutrophils to kill phagocytosed microorganisms (bacteria); This adherence elevates intracellular free calcium levels in humans. Upregulation of RAGE was not found after binding. | Diseases where AGE has been implicated (diabetes atherosclerosis, and Alzheimer's disease) |
T Cells | HMGB1 | RAGE activation is one of the early events in differentiation and proliferation of Th1+ cells | Arthritis |
B Cells | HMGB1-CpG DNA | Stimulates cytokine release along with TLR9 | Sepsis |
Macrophages, Monocytes | Any RAGE ligand | Inflammatory response is generated. Increased conversion of monocytes to macrophages. RAGE activation leads to destruction of macrophages. | Diabetes |
Dendritic Cells | HMGB1, some S100's | Antigen presenting capacity is unaffected. RAGE expression is upregulated after cellular activation. | Arthritis |