Palmitoylation of transforming growth factor-ß receptor-I by ZDHHCs
(2023) KIMM05 20231Department of Immunotechnology
- Abstract
- The transforming growth factor-ß (TGFß) family consists of proteins which control cell differentiation, growth, adhesion, migration, and death in multicellular eukaryotes. Due to its multiple roles, dysregulation of TGFß signaling can cause several diseases, such as cancer. A major factor regulating these networks are post translational modifications (PTMs) of involved proteins. A PTM that has got an increased attention in cancer research is palmitoylation, which is a reversible lipid posttranslational modification, catalyzed by the zinc finger DHHC-type containing (ZDHHC) protein family. In this study, we aimed to provide further insight into the role of the 23 mammal ZDHHCs in palmitoylation of TßRI, which is a type I receptor in the... (More)
- The transforming growth factor-ß (TGFß) family consists of proteins which control cell differentiation, growth, adhesion, migration, and death in multicellular eukaryotes. Due to its multiple roles, dysregulation of TGFß signaling can cause several diseases, such as cancer. A major factor regulating these networks are post translational modifications (PTMs) of involved proteins. A PTM that has got an increased attention in cancer research is palmitoylation, which is a reversible lipid posttranslational modification, catalyzed by the zinc finger DHHC-type containing (ZDHHC) protein family. In this study, we aimed to provide further insight into the role of the 23 mammal ZDHHCs in palmitoylation of TßRI, which is a type I receptor in the TGFß family. Acyl Resin Assisted Capture (Acyl RAC), a commonly used method to detect palmitoylated proteins, was used and our findings imply that ZDHHC 15 and 20 increase palmitoylation level of TßRI. To assess the impact of increased palmitoylation of TßRI on TGFß signaling, a functional assay with a TGFß responsive reporter was used. Our results showed that overexpression of ZDHHC15 and ZDHHC20 significantly decreased TGF-ß-dependent promoter activity. Since the response of advanced tumors to TGFß stimulation is reprogrammed, promoting unrestrained wound-healing, angiogenesis, and immune suppression as tumors progress, TGFß inhibitory therapies have arisen as a complement to the existing immunotherapies. Our results thus suggest ZDHHC15 and ZDHHC20 as possible candidates for future TGFß inhibitory therapeutics. (Less)
- Popular Abstract
- There are several causes of cancer. One is alterations in the signaling system that tells the cells to keep up with their housekeeping business, i.e., the functions the cells need to have to function properly. Some of these necessary cell functions are their ability to grow, divide and die at the right moment. One protein that helps cells with this, by communication trough signaling, is the transforming growth factor-ß receptor-I (TßRI). In tumor cells, the signal from TßRI is stronger than normal. This upregulation in signaling can be compared with a leader, demanding tumor cells to divide more than wanted and spread to tissues where the cells are not supposed to be. This ‘receptor leader’ also demands the immune system to quit its normal... (More)
- There are several causes of cancer. One is alterations in the signaling system that tells the cells to keep up with their housekeeping business, i.e., the functions the cells need to have to function properly. Some of these necessary cell functions are their ability to grow, divide and die at the right moment. One protein that helps cells with this, by communication trough signaling, is the transforming growth factor-ß receptor-I (TßRI). In tumor cells, the signal from TßRI is stronger than normal. This upregulation in signaling can be compared with a leader, demanding tumor cells to divide more than wanted and spread to tissues where the cells are not supposed to be. This ‘receptor leader’ also demands the immune system to quit its normal work as cancer cell killer, and instead help the cancer cells to spread. Therefore, research about how this upregulation, or ‘receptor leader demands’, can be hindered is of great importance. One factor that is known to alter TßRI signaling is structures that are added to the receptor after it has been produced (translated), so called post-translational modifications. One type of post-translational modification which got increased attention recently is palmitoylation. Palmitoylation is the process in which a 16 carbon long fatty acid (palmitate) is added to proteins. The proteins responsible for the palmitoylation are called zinc finger DHHC-type containing (ZDHHC) proteins and are protein acyltransferases (i.e., proteins that aid moving fatty acids from one molecule to another). Humans have 23 different ZDHHC protein acyltransferases and the aim with this master thesis was to examine palmitoylation of TßRI by these ‘fatty acid moving’- proteins and find out how palmitoylation affects TßRI signaling. To analyze this, cells were told to produce TßRI and the different ZDHHCs. The proteins were then extracted from the cells, to analyze if palmitoylation of TßRI had occurred. From an initial experiment, which examined every ZDHHC, ZDHHC 5, 10, 14, 15 and 20 were chosen for another experiment, to confirm the initial findings. From this second experiment it was confirmed that ZDHHC 10, 15 and 20 increase palmitoylation of TßRI. Following these experiments, it was examined if the increase of palmitoylation affects TßRI signaling, and it was concluded that ZDHHC 15 and 20 significantly decrease the signal. Since the aim with cancer therapeutics targeting TßRI is to decrease the upregulated signal in cancer cells, i.e., silencing ‘the receptor leader demands’, these two ZDHHCs provide two new candidates for future cancer therapeutics. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9120929
- author
- Mildner, Hedvig LU
- supervisor
- organization
- course
- KIMM05 20231
- year
- 2023
- type
- H2 - Master's Degree (Two Years)
- subject
- keywords
- Palmitoylation, TGFß, TßRI, ZDHHC, Palmitoyl acyltransferases
- language
- English
- id
- 9120929
- date added to LUP
- 2023-06-13 08:41:55
- date last changed
- 2023-06-13 08:41:55
@misc{9120929,
abstract = {{The transforming growth factor-ß (TGFß) family consists of proteins which control cell differentiation, growth, adhesion, migration, and death in multicellular eukaryotes. Due to its multiple roles, dysregulation of TGFß signaling can cause several diseases, such as cancer. A major factor regulating these networks are post translational modifications (PTMs) of involved proteins. A PTM that has got an increased attention in cancer research is palmitoylation, which is a reversible lipid posttranslational modification, catalyzed by the zinc finger DHHC-type containing (ZDHHC) protein family. In this study, we aimed to provide further insight into the role of the 23 mammal ZDHHCs in palmitoylation of TßRI, which is a type I receptor in the TGFß family. Acyl Resin Assisted Capture (Acyl RAC), a commonly used method to detect palmitoylated proteins, was used and our findings imply that ZDHHC 15 and 20 increase palmitoylation level of TßRI. To assess the impact of increased palmitoylation of TßRI on TGFß signaling, a functional assay with a TGFß responsive reporter was used. Our results showed that overexpression of ZDHHC15 and ZDHHC20 significantly decreased TGF-ß-dependent promoter activity. Since the response of advanced tumors to TGFß stimulation is reprogrammed, promoting unrestrained wound-healing, angiogenesis, and immune suppression as tumors progress, TGFß inhibitory therapies have arisen as a complement to the existing immunotherapies. Our results thus suggest ZDHHC15 and ZDHHC20 as possible candidates for future TGFß inhibitory therapeutics.}},
author = {{Mildner, Hedvig}},
language = {{eng}},
note = {{Student Paper}},
title = {{Palmitoylation of transforming growth factor-ß receptor-I by ZDHHCs}},
year = {{2023}},
}